Baclofen formulations and methods of minimizing patient exposure to metabolite variations

ABSTRACT

Baclofen formulations, including formulations that minimize variability between doses, that minimize variation in patient exposure baclofen metabolites, and are bioequivalent in regards to baclofen versus M1 metabolite ratios of baclofen tablets.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser.No.17/489,343 filed Sep. 29, 2021 which is hereby incorporated byreference in its entirety.

FIELD

This application relates to, among other things, baclofen formulations,particularly formulations that minimize variability between doses, andthat minimize variation in patient exposure baclofen metabolites.

BACKGROUND

Baclofen is a widely used anti-spasticity drug and was originallydiscovered in 1960 by Ciba Geigy. After initial development as apotential antiepileptic agent, it was re-introduced in 1971 as askeletal muscle relaxant. The original dosage form was an oral tabletand subsequently an intrathecal injection (not for parenteral use) andan oral liquid formulation were approved.

Over the last decades, as bioanalytical techniques improved, regulatoryagencies have required characterization of major metabolites(typically >10% exposure) of new drugs to better understand and controlfor metabolite-related pharmacology, toxicology, adverse effects, anddrug-drug interactions. In the case of baclofen while the dominant(reported as 15%) metabolite has been identified(3-(4-chlorophenyl)-4-hydroxybutyric acid, hereafter referred to as“metabolite 1,” or “M1”) and limited evaluation has suggested it isinactive, this does not address its potential full spectrum of potentialspecific and non-specific biological activity. Additionally, thecontribution of the metabolite to the safety, toxicology, or drug-druginteractions remain unknown. Thus while ‘generic’ forms of baclofen(matching the dosage form and route of administration of alreadyapproved baclofen presentations) are assumed to have exactly matchingmetabolite pharmacokinetics and therefore similar biological effects,this may not be the case for new dosage forms or routes ofadministration.

The only literature report of M1 pharmacokinetics was a study comparingracemic baclofen tablets (the approved form of baclofen is a racemic50:50 mix of R- and S-stereoisomers) and the pure R-stereoisomer only.Plasma concentrations of M1 were measured based on pooled 0-12 hoursamples, but without no characterization of C_(max), AUC, or t_(max).The study did however identify that M1 metabolite is a result ofstereoselective metabolism of only the S-isomer component followingracemic baclofen administration.

Thus there remains a need to develop new pharmaceutical presentations ofbaclofen that achieve matching parent baclofen to M1 exposure ratios asachieved by approved (tablet) forms.

SUMMARY

The invention provides baclofen formulations, particularly formulationsthat minimize variability between doses, and that minimize variation inpatient exposure baclofen metabolites.

Embodiments of the invention include pharmaceutical formulationscomprising: an effective amount of 4-amino-3-(4-chlorophenyl)butanoicacid) (baclofen), and one or more pharmaceutically acceptableexcipients; wherein the formulation is a mutiparticulate formulation;and wherein on administration to a patient produces3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in thepatient; wherein a ratio C_(max(baclofen)):C_(max(M1)) is A, andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) is B; and wherein administeringthe pharmaceutical formulation to the patient produces A and B valuesthat are within 10% of a ratio C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tablet formulationaccording to Baclofen Tablets monograph as defined by US Pharmacopeiaand containing an equal amount of baclofen.

Embodiments of the invention further include methods of treatingspasticity in a patient comprising: administering to the patient apharmaceutical formulation comprising: an effective amount of4-amino-3-(4-chlorophenyl)butanoic acid) (baclofen), and one or morepharmaceutically acceptable excipients; wherein the formulation is amutiparticulate formulation; and wherein on administration to a patientproduces 3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolitein the patient; wherein a ratio C_(max(baclofen)):C_(max(M1)) is A, andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) is B; and wherein administeringthe pharmaceutical formulation to the patient produces A and B valuesthat are within 10% of a ratio C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tablet formulationaccording to Baclofen Tablets monograph as defined by US Pharmacopeiaand containing an equal amount of baclofen.

In embodiments, administering the pharmaceutical formulation with orwithout water, or with soft foods or liquids, to the patient produces Aand B values that are greater than the ratioC_(max(baclofen)):C_(max(M1)) and AUC_((0-t)(baclofen)):AUC_((0-t)(M1))for a baclofen tablet formulation according to Baclofen Tablets asdefined by US Pharmacopeia monograph. In embodiments, administering thepharmaceutical formulation with or without water, or with soft foods orliquids, to the patient produces A and B values that are less than theratio C_(max(baclofen)):C_(max(M1)) and AUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tablet formulation according to BaclofenTablets as defined by US Pharmacopeia monograph.

In embodiments, administering a 20-mg dose of the pharmaceuticalformulation with or without water, or with soft foods or liquids, to thepatient produces a C(max)(baclofen) value of from about 274 ng/mL toabout 433 ng/mL. In embodiments, administering a 20-mg dose of thepharmaceutical formulation with or without water, or with soft foods orliquids, to the patient produces a C_((max)(M1)) value of from about 37ng/mL to about 75 ng/mL. In embodiments, administering a 20-mg dose ofthe pharmaceutical formulation with or without water, or with soft foodsor liquids, to the patient produces a ratioC_(max(baclofen)):C_(max(M1)) of from about 4 to about 11, such as fromabout 6.1 to about 7.5, or from about 6.2 to about 6.4.

In embodiments, administering a 20-mg dose of the pharmaceuticalformulation with or without water, or with soft foods or liquids, to thepatient produces a AUC_((0-t)(baclofen)) value of from about 1707 hng/mL to about 2896 h ng/mL. In embodiments, administering a 20-mg doseof the pharmaceutical formulation with or without water, or with softfoods or liquids, to the patient produces a AUC_((0-t)(M1)) value offrom about 461 hng/mL to about 1017 hng/mL. In embodiments,administering a 20-mg dose of the pharmaceutical formulation to thepatient produces a ratio AUC_((0-t)(baclofen)):AUC_((0-t)(M1)) of fromabout 2 to about 5, such as from about 2.8 to about 3.4, or from about3.0 to about 3.2.

In embodiments, the spasticity results from multiple sclerosis, and inembodiments, the spasticity is associated with at least one of flexorspasms, pain, clonus, and muscular rigidity. In embodiments, theeffective amount of baclofen is 20 mg. In embodiments, the spasticityresults from cerebral palsy, stroke, traumatic brain injury, spinal cordinjury, spinal cord disease, or combinations thereof.

In embodiments, methods of controlling exposure to baclofen metabolite3-(4-chlorophenyl)-4-hydroxybutyric acid in a patient comprise:administering to the patient a pharmaceutical formulation comprising aneffective amount of 4-amino-3-(4-chlorophenyl)butanoic acid) (baclofen),and one or more pharmaceutically acceptable excipients; wherein theformulation is a mutiparticulate formulation; and wherein onadministration to a patient produces 3-(4-chlorophenyl)-4-hydroxybutyricacid (M1) as a metabolite in the patient; and wherein the coefficient ofvariation for AUC_((0-t)(M1)) is 0.34 or less, such as 0.30 or less.

Additional features, advantages, and further embodiments of the presentdisclosure will be set forth in part in the description that follows,and in part will be apparent from the description, or may be learned bypractice of the present disclosure. The objectives and other advantagesof the present disclosure will be realized and attained by means of theelements and combinations particularly pointed out in the descriptionand claims.

The foregoing general description and the following detailed descriptionare exemplary and explanatory only to provide a further explanation ofthe present disclosure and are not restrictive of the scope of thesubject matter encompassed by the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the formation of 4-CPP at different storage timesfor various baclofen mortar treatment formulations with different E POlevels compared with amino acids.

FIG. 2 is a graph of the formation of 4-CPP at different storage timesfor various baclofen compression formulations with different E PO levelscompared with amino acids.

FIG. 3 is a graph of the formation of 4-CPP at different storage timesfor various baclofen ethanol granulation formulations with different EPO levels compared with amino acids.

FIG. 4 is a graph of the formation of 4-CPP at different storage timesfor various baclofen water granulation formulations with different E POlevels compared with amino acids.

FIG. 5 is a graph of the formation of Impurity A at different storagetimes for various gabapentin mortar treatment formulations withdifferent EPO levels compared with amino acids.

FIG. 6 is a graph of the formation of Impurity A at different storagetimes for various gabapentin compression formulations with different EPO levels compared with amino acids.

FIG. 7 is a graph of the formation of Impurity A at different storagetimes for various gabapentin ethanol granulation formulations withdifferent E PO levels compared with amino acids.

FIG. 8 is a graph of the formation of Impurity A at different storagetimes for various gabapentin water granulation formulations withdifferent E PO levels compared with amino acids.

FIG. 9 is a graph of the formation of Impurity A at different storagetimes for various pregabalin mortar treatment formulations withdifferent EPO levels compared with amino acids.

FIG. 10 is a graph of the formation of Impurity A at different storagetimes for various pregabalin compression formulations with different EPO levels compared with amino acids.

FIG. 11 is a graph of the formation of Impurity A at different storagetimes for various pregabalin ethanol granulation formulations withdifferent E PO levels compared with amino acids.

FIG. 12 is a graph of the formation of Impurity A at different storagetimes for various pregabalin water granulation formulations withdifferent E PO levels compared with amino acids.

FIG. 13 shows IR spectra of 40:60 and 60:40 E PO/baclofen mixtures.

FIG. 14 shows IR spectra of 80:20 and 85:15 E PO/baclofen mixtures.

FIG. 15 shows IR spectra of a 90:10 E PO/baclofen mixture and 100%baclofen.

FIG. 16 shows IR spectra of E PO/gabapentin and E PO/pregabalinmixtures.

FIG. 17 shows particle size distribution by sieve analysis of twobaclofen granule batches.

FIG. 18 shows particle size distribution by sieve analysis of threebaclofen final blends.

FIG. 19 shows dissolution profiles for micronized and non-micronized API(baclofen) raw material, without further processing, compared to acommercial tablet (made by ratiopharm) and two granule formulations, oneof which included micronized baclofen and the other of which includednon-micronized baclofen.

DETAILED DESCRIPTION

The particulars shown herein are by way of example and for purposes ofillustrative discussion of the various embodiments of the presentdisclosure only, and provide what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the disclosed subject matter. In this regard, no attempt is made toshow details of the disclosed subject matter in more detail than isnecessary for a fundamental understanding of the disclosure, thedescription making apparent to those skilled in the art how the severalforms of the disclosure may be embodied in practice.

The following disclosure refers to more detailed embodiments, withoccasional reference to the accompanying figures. The disclosed subjectmatter, however, may be embodied in different forms and should not beconstrued as limited to the embodiments set forth herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription herein is for describing particular embodiments only and isnot intended to be limiting. As used in the specification and claims,the singular forms “a,” “an,” and “the” are intended to include theplural forms as well, unless the context clearly indicates otherwise.Also, the phrases “at least one” and “one or more” are intended to beinterchangeable, and their use are not intended to limit the scope ofany described or claimed feature preceded by “a,” “an,” and “the” to asingular form.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, unless otherwise indicated.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and claims areapproximations that may vary depending upon the desired propertiessought to be obtained by a particular embodiment. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldbe construed in light of the number of significant digits and ordinaryrounding approaches.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the disclosed subject matter are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin the method used to obtain the value. Every numerical range giventhroughout this specification includes every narrower numerical rangethat falls within such broader numerical range, as if such narrowernumerical ranges were all expressly written herein.

Reference to compounds in the specification includes esters and salts ofsuch compounds. Thus, even if not explicitly disclosed, such esters andsalts are contemplated and encompassed by reference to the compoundsthemselves.

All percent measurements in this application, unless otherwise stated,are measured by weight based upon 100% of a given sample weight. Thus,for example, 30% represents 30 weight parts out of every 100 weightparts of the sample.

The present disclosure relates, in part, to a composition comprising anactive ingredient, and a stabilizer. The composition may be apharmaceutical composition.

A “pharmaceutical composition” as used herein means a compositioncomprising an active ingredient and at least one pharmaceuticallyacceptable excipient. As used herein, the term “pharmaceuticallyacceptable excipient” means a compound or ingredient that is compatiblewith the other ingredients in a pharmaceutical formulation and notinjurious to an intended subject when administered in normal ortherapeutically effective amounts. As used herein, an “intended subject”includes animals and/or humans. The terms “patient” and “subject” may beused interchangeably.

Suitable excipients are known to those of skill in the art and examplesare described, for example, in the Handbook of Pharmaceutical Excipients(Kibbe (ed.), 3rd Edition (2000), American Pharmaceutical Association,Washington, D.C.), and Remington's Pharmaceutical Sciences (Gennaro(ed.), 20th edition (2000), Mack Publishing, Inc., Easton, Pa.), which,for their disclosures relating to excipients and dosage forms, areincorporated herein by reference. Examples of excipients include but arenot limited to fillers, extenders, diluents, wetting agents, solvents,emulsifiers, preservatives, absorption enhancers, sustained-releasematrices, starches, sugars, microcrystalline cellulose, granulatingagents, lubricants, binders, disintegrating agents, coloring agents,release agents, coating agents, sweetening agents, flavoring agents,perfuming agents, antioxidants, plasticizers, gelling agents,thickeners, hardeners, setting agents, suspending agents, surfactants,humectants, carriers, stabilizers, and combinations thereof.

The present disclosure includes a large number and variety of componentsthat are contemplated for inclusion in the pharmaceutical formulations.It should be recognized that when the inventors expressly contemplateincluding such components, they also expressly contemplate excludingsuch components. Thus, all components disclosed herein are expresslycontemplated for exclusion as well.

As used herein, “active ingredient” is any component of the compositionintended to furnish pharmacological activity or other direct effect inthe diagnosis, cure, mitigation, treatment, or prevention of disease, orto affect the structure or any function of the body of the intendedsubject. Active ingredients include those components of the compositionthat may undergo chemical change during the manufacture of thecomposition and be present in a finished composition in a modified formintended to furnish the specified activity or effect. Active ingredientsalso include those components of the finished composition that during orafter administration of the finished drug product to the intended usermay undergo chemical change to a modified form intended to furnish thespecified activity or effect. For example, the active ingredient can bea pharmaceutically acceptable salt of the component that furnishes thespecified activity or effect.

As used herein, the term “pharmaceutically acceptable salt” includessalts that are physiologically tolerated by the intended subject. Suchsalts are typically prepared from an inorganic and/or organic acid.Examples of suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, and phosphoric acid. Organic acids may bealiphatic, aromatic, carboxylic, and/or sulfonic acids. Suitable organicacids include formic, acetic, propionic, succinic, camphorsulfonic,citric, fumaric, gluconic, lactic, malic, mucic, tartaric,para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic,benzoic, anthranilic, salicylic, phenylacetic, mandelic, pamoic,methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic(besylate), stearic, sulfanilic, alginic, galacturonic, and the like.

The composition may contain only one active ingredient, or more than oneactive ingredient, such as two, three, four, five, six, seven, eight, ornine active ingredients, or more than nine active ingredients.

The active ingredient can be selected from among active pharmaceuticalingredients (APIs). An API is a substance or mixture of substancesintended to be used in the manufacture of a pharmaceutical product andthat, when used in the production of a pharmaceutical product, becomesan active ingredient of the pharmaceutical product. Such substances areintended to furnish pharmacological activity or other direct effect inthe diagnosis, cure, mitigation, treatment, or prevention of disease orto affect the structure or function of the body of the intended subject.

In some embodiments, the active ingredient is a lactam-formingingredient, such as a 4-amino-3-substituted-butanoic acid derivative.Examples of 4-amino-3-substituted-butanoic acid derivatives includebaclofen, gabapentin, and pregabalin.

In some embodiments, the active ingredient is selected from baclofen(4-amino-3-(4-chlorophenyl)butanoic acid) and its pharmaceuticallyacceptable salts. Baclofen has the following structure:

The active ingredient, such as baclofen, can be in any form, such asgranular, powder, or micronized form (e.g., Micronized, USP fromPolpharma). Without being bound to a particular scientific theory, theinventors hypothesize that smaller particle size results in largersurface area and increases the contact area between the baclofen and thestabilizer, improving the ability of the stabilizer to interact with andstabilize the baclofen. The active ingredient may be milled to reducethe particle size. However, for purposes of dissolution testing, asshown in the Examples below, micronization had no effect on dissolutionresults of granule formulations. Because micronization providedstability advantages, micronized baclofen is preferred.

The average particle size of the active ingredient will generally beless than 1000 μm, such as less than 750 μm, less than 500 μm, less than250 μm, or less than 125 μm. The average particle size may be largerthan 25 μm, or larger than 50 μm, or larger than 75 μm, or larger than100 μm, or larger than 125 μm, or larger than 150 μm. The averageparticle size will generally range from about 50 to about 750 μm, orfrom about 75 to about 500 μm, or from about 100 to about 200 μm. Theaverage particle size is not critical, as long as the stabilizing effectis produced.

In addition to the active ingredient, the composition may comprise astabilizer that inhibits the formation of the lactam autodegradationproduct of a 4-amino-3-substituted-butanoic acid derivative, or itspharmaceutically acceptable salt, when used as an active ingredient. Themain lactam autodegradation product of baclofen is4-(4-chlorophenyl)-2-pyrrolidine (4-CPP) (also referred to herein as“Impurity A”).

As used herein, the term “stabilizer” refers to the compound orcompounds in the composition that functions to reduce or inhibit theformation of the lactam autodegradation product of a4-amino-3-substituted-butanoic acid derivative or its pharmaceuticallyacceptable salt. In embodiments, the term “stabilizer” excludes thea-amino acids described by U.S. Pat. No. 7,309,719 as stabilizers,including any of the following:

neutral α-amino acids including glycine, phenylglycine,hydroxyphenylglycine, dihydroxyphenylglycine, L-alanine,hydroxy-L-alanine, L-leucine, hydroxy-L-leucine, dihydroxy-L-leucine,L-norleucine, methylene-L-norleucine, L-ketonorleucine, L-isoleucine,hydroxy-L-isoleucine, dihydroxy-L-isoleucine, L-valine,hydroxy-L-valine, L-isovaline, L-norvaline, hydroxy-L-norvaline,hydroxy-L-ketonorvaline, L-methionine, L-homomethionine, L-ethionine,L-threonine, acetyl-L-threonine, L-tryptophan, hydroxy-L-tryptophan,methyl-L-tryptophan, L-tyrosine, hydroxy-L-tyrosine, methyl-L-tyrosine,bromo-L-tyrosine, dibromo-L-tyrosine, 3,5-diiodo-L-tyrosine,acetyl-L-tyrosine, chloro-L-tyrosine, L-m-tyrosine, L-levodopa,L-methyldopa, L-thyroxine, L-serine, acetyl-L-serine, L-homoserine,acetyl-L-homoserine, ethyl-L-homoserine, propyl-L-homoserine,butyl-L-homoserine, L-cystine, L-homocystine, methyl-L-cystein,allyl-L-cysteine, propyl-L-cysteine, L-phenylalanine,dihydro-L-phenylalanine, hydroxymethyl-L-phenylalanine, L-aminobutyricacid, L-aminoisobutyric acid, L-ketoaminobutyric acid,dichloro-L-aminobutyric acid, dihydroxy-L-aminobutyric acid,phenyl-L-aminobutyric acid, L-aminovaleric acid, L-aminohydroxyvalericacid, dihydroxy-L-aminovaleric acid, L-aminoisovaleric acid,L-aminohexanoic acid, methyl-L-aminohexanoic acid, L-aminoheptanoicacid, L-aminooctanoic acid, citrulline, and the D- and DL-forms thereof;

acidic α-amino acids including L-aspartic acid, L-glutamic acid,L-carbocysteine, L-aminoglutaric acid, L-aminosuccinic acid,L-aminoadipic acid, L-aminopimelic acid, hydroxy-L-aminopimelic acid,methyl-L-aspartic acid, hydroxy-L-aspartic acid, methyl-L-glutamic acid,methylhydroxy-L-glutamic acid, L-methyleneglutamic acid,hydroxy-L-glutamic acid, dihydroxy-L-glutamic acid,hydroxy-L-aminoadipic acid, and the like, and the D- and DL-formsthereof;

basic a-amino acids including L-arginine, L-lysine, L-ornithine,L-canavanine, L-canaline, hydroxy-L-lysine, L-homoarginine,hydroxy-L-homoarginine, hydroxy-L-omithine, L-diaminopropionic acid,L-diaminohexanoic acid, L-diaminobutyric acid. L-diaminovaleric acid,L-diaminoheptanoic acid, L-diaminooctanoic acid, and the like and the D-and DL-forms thereof; and

α,Ω-diaminodicarboxylic acids including diaminosuccinic acid,diaminoglutaric acid, diaminoadipic acid, diaminopimelic acid, and thelike.

The stabilizer may be selected from polymethacrylate-based copolymers,which may include anionic, cationic, and neutral copolymers based onmethacrylic acid and methacrylic/acrylic esters or their derivatives,including, but not limited to, amino methacrylate copolymers, methylmethacrylate copolymers, dimethylaminoethyl methacrylate copolymers, andbutyl methacrylate copolymers, in particular, methacrylic estercopolymer, methacrylic acid copolymer, ammonioalkyl methacrylatecopolymer, and amino alkyl methacrylate copolymer. In some embodiments,the stabilizer ispoly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate.

The manner of mixing the active ingredient and stabilizer is notcritical, and can be done in any pharmaceutically acceptable manner.Tumbler, convective, and fluidization blenders are useful, for example,where the active ingredient and stabilizer are mixed in dry form;agitators and heavy mixers, including high shear mixers, are useful, forexample, where the active ingredient and stabilizer are mixed with aliquid. The composition can be made into a granular formulation, throughwet or dry granulation, depending on the desired dosage form, releaserate, or other manufacturing preferences.

Wet granulation solvents can be selected based on the preference of themanufacturer and are not critical. Examples include, but are not limitedto, ethanol and water. If desired, binders such as PVP can also beincluded.

In some embodiments, the formulation is manufactured in such a way as tomaximize the interaction between molecules of the active ingredient andmolecules of the stabilizer. This may take the form of a matrixformulation in which the active ingredient and stabilizer are intimatelymixed, and may be based on starting materials in which the activeingredient is milled to increase its surface area and interaction withthe stabilizer. Without wishing to be bound by any particular theory ofoperation, it appears that the stabilizing effect is through a chemicalinteraction between the stabilizing agent and the active ingredient.Thus, steps that increase the ability of the stabilizing agent andactive ingredient are believed to be helpful in maximizing thestabilizing effect.

In a wet granulation process, the active agent and stabilizer can beintimately mixed by dry blending, followed by adding a granulationsolvent. This process is intended to improve the interaction between theactive ingredient and the stabilizer, and is distinguished fromprocesses in which a polymer is first dissolved in a solvent, followedby mixing with a dry active ingredient.

Those skilled in the art will readily recognize that a matrix having theabove-described intimate mixture of active ingredient and stabilizer isstructurally different from coated or encapsulated active ingredients,as such are commonly understood in the art. That is, a coated orencapsulated product is one in which a core containing the activeingredient is completely encased in or covered by the coating material.Such a structure does not maximize the interaction between the activeingredient and stabilizer.

On the other hand, an intimate mixture of stabilizer and activeingredient in matrix granules can have some active ingredient at theouter periphery of the granule that is not completely covered by thestabilizer. Such a matrix in accordance with the present disclosure isnot designed to coat or encase the active ingredient, but is ratherintended to maximize interaction between active ingredient andstabilizer. However, to be clear, the inventors contemplate thatgranules formed from an intimate mixture of stabilizer and activeingredient (i.e., a stabilized composition of the active ingredient) canbe further coated with a coating material (examples of which arediscussed in more detail below) for a variety of effects.

The composition comprising the intimate mixture of active ingredient andstabilizer may contain a weight ratio of the stabilizer to the activeingredient in a range from about 1:100 to about 20:1, such as from about1:10 to about 10:1, about 9:1 to about 20:1, about 0.01:1 to about 7:1,about 6:1 to about 13:1, about 12:1 to about 20:1, about 0.5:1 to about10:1, about 1:1 to about 7:1, about 1.5:1 to about 18:1, about 1.6:1 toabout 20:1, or about 1.8:1 to about 7.5:1, with specific examples being1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.4:1, 2.6:1, 3:1, 4:1, and 5:1.The lower limit of the range may be any value from about 0.01:1 orgreater, and the upper limit of the range may independently be any valuefrom about 20:1 or less, so long as the lower limit is not greater thanthe upper limit.

The composition may be formulated by varying the ratios of the activeingredient and stabilizer, both in powder form. Alternatively, “activegranules” may be formulated to include both active ingredient andstabilizer, and “placebo granules” may be formulated without activeingredient, and the final ratios may be varied by adjusting ratios ofthe two types of granules. In some embodiments, the placebo granulescontain approximately the same amount of stabilizer and excipientspresent in the active granules (i.e. granules of the intimate mixture ofactive ingredient and stabilizer). The missing active ingredient may besubstituted with an additional amount of one of the excipients in anamount equal to that of the missing active ingredient to maintain theratios of the other ingredients in the placebo granules. The placebogranules may have the same average diameter as the active granules.Different strengths of dosage forms can be obtained my mixingnon-placebo granules with placebo granules.

Pharmaceutical compositions are typically provided in dosage forms thatare suitable for administration to an intended subject by a desiredroute. Various dosage forms are described below, but are not meant toinclude all possible choices. One of skill in the art is familiar withthe various dosage forms that are suitable for use, as described, forexample, in Remington's Pharmaceutical Sciences, which has beenincorporated by reference above. The most suitable route in any givencase will depend on the nature and severity of the disease and/orcondition being prevented, treated, and/or managed. For example,pharmaceutical compositions may be formulated for administration orally,nasally, rectally, intravaginally, parenterally, intracisternally, andtopically, including buccally and sublingually.

Formulations for oral administration include capsules, cachets, pills,tablets, lozenges (using a flavored basis, usually sucrose and acacia ortragacanth), powders, granules, suspensions in an aqueous or non-aqueousliquid, oil-in-water or water-in-oil liquid emulsions, elixirs, syrups,pastilles (using an inert base, such as gelatin and glycerin, or sucroseand acacia), mouth washes, pastes, and the like; each containing apredetermined amount of stabilizer and baclofen, a derivative thereof,or a pharmaceutically acceptable salt thereof, to provide a therapeuticamount of the baclofen in one or more doses.

Liquid dosage forms may include the stabilized formulations according tothe present invention in suspension form. For example, coated oruncoated stabilized granules may be suspended in a liquid foradministration. A suspension may be manufactured as a suspension orreconstituted by an end user (e.g., doctor, pharmacist, patient) as asuspension for administration. The inventors also contemplate thereconstitution of a stabilized formulation by dissolving a stabilizedformulation in a liquid that dissolves the stabilized formulation. Thistoo could be mixed by the manufacturer, or by an end user.

In solid dosage forms for oral administration (capsules, tablets, pills,powders, granules and the like), the active ingredient, derivativethereof, or pharmaceutically acceptable salt thereof can be mixed withone or more pharmaceutically-acceptable excipients, including carriers,such as sodium citrate or dicalcium phosphate; fillers or extenders,such as starches, spray-dried or anhydrous lactose, sucrose, glucose,mannitol, dextrose, sorbitol, xylitol, cellulose, dehydrated oranhydrous dibasic calcium phosphate, and/or silicic acid; binders, suchas acacia, alginic acid, carboxymethylcellulose (sodium), cellulose(microcrystalline), dextrin, ethylcellulose, gelatin, glucose (liquid),guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose, polyethylene oxide, povidone, starch (pregelatinized)or syrup; humectants, such as glycerol; disintegrating agents, such asagar, calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, pregelatinized starch, sodium starch glycolate, crosslinkedpovidone, crosslinked sodium carboxymethylcellulose, clays,microcrystalline cellulose, alginates, gums, and/or sodium carbonate;solution retarding agents, such as paraffin; absorption accelerators,such as quaternary ammonium compounds; wetting agents, such as cetylalcohol or glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, steric acid, sodium stearylfumarate, magnesium lauryl sulfate, hydrogenated vegetable oil, and/orsodium lauryl sulfate; glidants, such as calcium silicate, magnesiumsilicate, colloidal anhydrous silica, and/or talc; flavoring agents,such as synthetic flavor oils and flavoring aromatics, natural oils,extracts from plant leaves, flowers, and fruits, including cinnamon oil,oil of wintergreen, peppermint oils, bay oil, anise oil, eucalyptus,thyme oil, vanilla, citrus oil (e.g., lemon, orange, grape, lime, andgrapefruit), fruit essences (e.g., apple, banana, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot, as so forth);coloring agents and/or pigments, such as titanium dioxide and/or dyesapproved for use in food and pharmaceuticals; buffering agents;dispersing agents; preservatives; and/or diluents.

Solid dosage forms may optionally be scored or prepared with coatingsand shells, such as enteric coatings, and coatings for modifying therate of release, examples of which are well known in thepharmaceutical-formulating art. For example, such coatings may comprisesodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, methacrylic acid copolymer, methylcellulose, polyethyleneglycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide,wax, or zein. The coating material may further comprise anti-adhesives,such as talc; plasticizers, such as castor oil, diacetylatedmonoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate;opacifiers, such as titanium dioxide; and/or coloring agents and/orpigments. The coating process may be carried out by any suitable means,for example, by using a perforated pan system such as the GLATT™,ACCELACOTA™, and/or HICOATER™ apparatuses.

Tablets may be formed by any suitable process, examples of which areknown to those of ordinary skill in the art. For example, theingredients may be dry-granulated or wet-granulated, such as with wateror ethanol, by mixing in a suitable apparatus before tableting. Granulesof the ingredients to be tableted may also be prepared using suitablespray/fluidization or extrusion/spheronization techniques.

With quick-release tablets, the choice of excipients generally allows afast dissolution. The tablets may be conventional instant releasetablets designed to be taken whole in the typical administration manner(i.e., with a sufficient amount of water to facilitate swallowing).Alternatively, the tablets may be formulated with suitable excipients toact as a fast dissolving and/or fast melting tablet in the oral cavity.Xylitol is especially useful as an excipient in orally disintegratingformulations. Also, the tablet can be in the form of a chewable oreffervescent dosage form. With effervescent dosage forms, the tablet istypically added to a suitable liquid that causes it to disintegrate,dissolve, and/or disperse.

Tablets typically are designed to have an appropriate hardness andfriability to facilitate manufacture on an industrial scale usingequipment to produce tablets at high speed. Also, the tablets can bepacked or filled in all kinds of containers. If the tablet has aninsufficient hardness or is friable, the tablet that is taken by thesubject or patient may be broken or crumbled into powder. Because ofthis insufficient hardness or friability, the subject or patient can nolonger be certain that the amount of the dose is correct. The hardnessof tablets, disintegration rate, and other properties can be influencedby the shape of the tablets. Tablets may be circular, oblate, oblong, orany other pharmaceutically acceptable shape.

Solid compositions may be encapsulated in a soft or hard gelatin capsuleusing any of the excipients described here. For example, an encapsulateddosage form may include fillers, such as lactose and microcrystalline;glidants, such as colloidal silicon dioxide and talc; lubricants, suchas magnesium stearate; and disintegrating agents, such as starch (e.g.,maize starch). Using capsule filling equipment, the ingredients to beencapsulated can be milled together, sieved, mixed, packed together, andthen delivered into a capsule.

The compositions include immediate release, modified release, sustainedrelease, and controlled release formulations and dosage forms, and anycombination thereof.

As used herein, the term “immediate release” describes a formulation ordosage form that releases the drug upon dissolution, without significantdelay. In some embodiments, such formulations would release the drug inthe upper GI, including the mouth, esophagus, and/or stomach.

Different types of modified dosage forms are briefly described below. Amore detailed discussion of such forms may also be found in, forexample, The Handbook of Pharmaceutical Controlled Release Technology,D. L. Wise (ed.), Marcel Dekker, Inc., New York (2000); and also inTreatise on Controlled Drug Delivery: Fundamentals, Optimization, andApplications, A. Kydonieus (ed.), Marcel Dekker, Inc., New York, (1992),the relevant contents of each of which is hereby incorporated byreference for this purpose. Examples of modified release dosage formsare also described, for example, in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, thedisclosures of which, for their discussions of pharmaceuticalformulations, are incorporated herein by reference.

As used herein, the phrase “modified-release” describes a formulation ordosage form that achieves a desired release of the drug from theformulation. For example, a modified-release formulation may extend theinfluence or effect of a therapeutically effective dose of apharmaceutically active compound in a patient. Such formulations arereferred to herein as “extended-release formulations.” In addition tomaintaining therapeutic levels of the pharmaceutically active compound,a modified-release formulation may also be designed to delay the releaseof the active compound for a specified period. Such compounds arereferred to herein as “delayed onset” of “delayed release” formulationsor dosage forms. Still further, modified-release formulations mayexhibit properties of both delayed and extended release formulations,and thus be referred to as “delayed-onset, extended-release”formulations.

Advantages of modified-release formulations may include extendedactivity of the drug, reduced dosage frequency, increased patientcompliance, and the ability to deliver the drug to specific sites in theintestinal tract. Suitable components (e.g., polymers, excipients, etc.)for use in modified-release formulations, and methods of producing thesame, are also described, e.g., in U.S. Pat. No. 4,863,742, which isincorporated by reference for these purposes.

Modified release formulations can be provided as matrix-based dosageforms. Matrix formulations may include hydrophilic, e.g., water-soluble,and/or hydrophobic, e.g., water-insoluble, polymers. Matrix formulationsmay optionally be prepared with functional coatings, which may beenteric, e.g., exhibiting a pH-dependent solubility, or non-enteric,e.g., exhibiting a pH-independent solubility.

Matrix formulations may be prepared by using, for example, directcompression or wet granulation. A functional coating, as noted above,may then be applied. Additionally, a barrier or sealant coat may beapplied over a matrix tablet core prior to application of a functionalcoating. The barrier or sealant coat may serve the purpose of separatingan active ingredient from a functional coating, which may interact withthe active ingredient, or it may prevent moisture from contacting theactive ingredient. Details of barriers and sealants are provided below.There is no limit on the manners in which the various features describedherein may be combined, provided that the formulation is a stabilizedformulation.

The inventors contemplate that a matrix composition of the stabilizedformulation may be formed by mixing the active ingredient with astabilizer, and forming that composition into a solid dosage form, suchas a multi-unit-containing capsule or a monolithic tablet. The inventorsalso contemplate the use of other excipients, such as polymers, that maybe used to modify the release of the active agent from the formulation.

In a matrix-based dosage form, for example, the active ingredient,stabilizer, and optional pharmaceutically acceptable excipients may bedispersed within one or more polymers. The one or more polymerstypically comprise at least one water-soluble polymer and/or at leastone water-insoluble polymer. The active ingredient may be released fromthe dosage form by diffusion and/or erosion.

Water-soluble polymers include polyvinyl alcohol, polyvinylpyrrolidone,methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,or polyethylene glycol, and/or mixtures thereof.

Water-insoluble polymers include ethylcellulose, cellulose acetatecellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate,poly(methyl) in more than one group; the classifications are descriptiveonly, and not intended to limit any use of a particular excipient.

The amounts and types of polymers, and the ratio of water-solublepolymers to water-insoluble polymers in formulations can be selected toachieve a desired release profile of the active ingredient, a derivativethereof or a pharmaceutically acceptable salt thereof. For example, byincreasing the amount of water-insoluble-polymer relative to the amountof water-soluble polymer, the release of the drug may be delayed orslowed. This is due, in part, to an increased impermeability of thepolymeric matrix, and, in some cases, to a decreased rate of erosionduring transit through the GI tract.

Modified release formulations may also be provided asmembrane-controlled formulations. Membrane controlled formulations canbe made by preparing a rapid release core, which may be a monolithic(e.g., tablet) or multi-unit (e.g., pellet) type, and coating the corewith a membrane. The membrane-controlled core can then be further coatedwith a functional coating. In between the membrane-controlled core andfunctional coating, a barrier or sealant may be applied. Details ofmembrane-controlled dosage forms are provided below.

Modified release formulations can comprise at least one polymericmaterial, which may be applied as a membrane coating to activeingredient-containing granule cores. Suitable water-soluble polymersinclude polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethyleneglycol, and/or mixtures thereof.

Suitable water-insoluble polymers include ethylcellulose, celluloseacetate cellulose propionate, cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate, cellulose triacetate,poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), and poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate),poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropylacrylate), poly(isobutyl acrylate), poly(octadecyl acrylate),poly(ethylene), poly(ethylene) low density, poly(ethylene) high density,poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutylether), poly(vinyl acetate), poly(vinyl chloride) or polyurethane,and/or mixtures thereof. Methacrylate copolymers, such as EUDRAGIT™polymers (available from Rohm Pharma) are polymeric lacquer substancesbased on acrylates and/or methacrylates. A variety of methacrylatecopolymers are readily available, examples of which are described above.Certain methacrylate copolymers may serve as stabilizing agents in thepresent invention, but methacrylate copolymers may also be used tomodify the release of the active ingredient. In this regard, it shouldbe noted that not all methacrylate copolymers are believed to impart astabilizing effect, but all methacrylate copolymers are believed to beuseful for modifying the release of the active ingredient from theformulation.

The membrane coating may comprise a polymeric material comprising amajor proportion (i.e., greater than 50% of the total polymeric content)of one or more pharmaceutically acceptable water-soluble polymers, andoptionally a minor proportion (i.e., less than 50% of the totalpolymeric content) of one or more pharmaceutically acceptablewater-insoluble polymers. Alternatively, the membrane coating maycomprise a polymeric material comprising a major proportion (i.e.,greater than 50% of the total polymeric content) of one or morepharmaceutically acceptable water-insoluble polymers, and optionally aminor proportion (i.e., less than 50% of the total polymeric content) ofone or more pharmaceutically acceptable water-soluble polymers.

The coating membrane may further comprise at least one soluble excipientto increase the permeability of the polymeric material. Suitably, thesoluble excipient is selected from among a soluble polymer, asurfactant, an alkali metal salt, an organic acid, a sugar, and a sugaralcohol. Such soluble excipients include polyvinyl pyrrolidone,polyethylene glycol, sodium chloride, surfactants such as sodium laurylsulfate and polysorbates, organic acids such as acetic acid, adipicacid, citric acid, fumaric acid, glutaric acid, malic acid, succinicacid, and tartaric acid, sugars such as dextrose, fructose, glucose,lactose and sucrose, sugar alcohols such as lactitol, maltitol,mannitol, sorbitol and xylitol, xanthan gum, dextrins, andmaltodextrins. In some embodiments, polyvinyl pyrrolidone, mannitol,and/or polyethylene glycol can be used as soluble excipients. Thesoluble excipient(s) may be used in an amount of from about 1% to about10% by weight, based on the total dry weight of the polymer.

In some embodiments, the polymeric material comprises at least onewater-insoluble polymer, which is also insoluble in gastrointestinalfluids, and at least one water-soluble pore-forming compound. Forexample, the water-insoluble polymer may comprise a terpolymer ofpolyvinylchloride, polyvinylacetate, and/or polyvinylalcohol. Suitablewater-soluble pore-forming compounds include saccharose, sodiumchloride, potassium chloride, polyvinylpyrrolidone, and/orpolyethyleneglycol. The pore-forming compounds may be uniformly orrandomly distributed throughout the water-insoluble polymer. Typically,the pore-forming compounds comprise about 1 part to about 35 parts foreach about 1 to about 10 parts of the water-insoluble polymers.

When such dosage forms come in to contact with the dissolution media(e.g., intestinal fluids), the pore-forming compounds within thepolymeric material dissolve to produce a porous structure through whichthe drug diffuses. Such formulations are described in more detail inU.S. Pat. No. 4,557,925, which relevant part is incorporated herein byreference for this purpose. The porous membrane may also be coated withan enteric coating, as described herein, to inhibit release in thestomach.

The polymeric material may also include one or more auxiliary agentssuch as fillers, plasticizers, and/or anti-foaming agents.Representative fillers include talc, fumed silica, glycerylmonostearate, magnesium stearate, calcium stearate, kaolin, colloidalsilica, gypsum, micronized silica, and magnesium trisilicate. Thequantity of filler used typically ranges from about 2% to about 300% byweight, and can range from about 20 to about 100%, based on the totaldry weight of the polymer. In one embodiment, talc is the filler.

Coating membranes, and functional coatings as well, can also include amaterial that improves the processing of the polymers. Such materialsare generally referred to as plasticizers and include, for example,adipates, azelates, benzoates, citrates, isoebucates, phthalates,sebacates, stearates and glycols. Representative plasticizers includeacetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyltartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethylglycolate, glycerin, ethylene glycol, propylene glycol, triacetincitrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetylmonoglyceride, polyethylene glycols, castor oil, triethyl citrate,polyhydric alcohols, acetate esters, glycerol triacetate, acetyltriethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate,epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate,di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate,di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyltrimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate,di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, andglyceryl monocaprate. In one embodiment, the plasticizer is dibutylsebacate. The amount of plasticizer used in the polymeric materialtypically ranges from about 10% to about 50%, for example, about 10%,20%, 30%, 40%, or 50%, based on the weight of the dry polymer.

Anti-foaming agents can also be included. The amount of anti-foamingagent used typically is from about 0% to about 0.5% of the finalformulation.

The amount of polymer used in membrane-controlled formulations istypically adjusted to achieve the desired drug delivery properties,including the amount of drug to be delivered, the rate and location ofdrug delivery, the time delay of drug release, and the size of themultiparticulates in the formulation. The amount of polymer appliedtypically provides an about 10% to about 100% weight gain to the cores,such as from about 25% to about 70%.

The combination of all solid components of the polymeric material,including co-polymers, fillers, plasticizers, and optional excipientsand processing aids, typically provides an about 10% to about 450%weight gain on the cores, such as from about 30% to about 160%.

The polymeric material can be applied by any known method, for example,by spraying using a fluidized bed coater (e.g., Wurster coating) or pancoating, or spray drying system. Coated cores are typically dried orcured after application of the polymeric material. Curing means that themultiparticulates are held at a controlled temperature for a timesufficient to provide stable release rates. Curing can be performed, forexample, in an oven or in a fluid bed drier. Curing can be carried outat any temperature above room temperature.

A sealant or barrier can also be applied to the polymeric coating. Asealant or barrier layer may also be applied to the core prior toapplying the polymeric material. A sealant or barrier layer is notintended to modify the release of baclofen, a derivative thereof or apharmaceutically acceptable salt. Suitable sealants or barriers arepermeable or soluble agents such as hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxypropyl ethylcellulose, and xanthan gum.

Other agents can be added to improve the processability of the sealantor barrier layer. Such agents include talc, colloidal silica, polyvinylalcohol, titanium dioxide, micronized silica, fumed silica, glycerolmonostearate, magnesium trisilicate and magnesium stearate, or a mixturethereof. The sealant or barrier layer can be applied from solution(e.g., aqueous) or suspension using any known means, such as a fluidizedbed coater (e.g., Wurster coating) or pan coating system. Suitablesealants or barriers include, for example, OPADRY WHITE Y-1-7000 andOPADRY OY/B/28920 WHITE, each of which is available from ColorconLimited, England.

The composition may be an oral dosage form containing amulti-particulate active ingredient in the form of caplets, capsules,particles for suspension prior to dosing, sachets, or tablets. When thedosage form is in the form of tablets, the tablets may be disintegratingtablets, fast dissolving tablets, effervescent tablets, fast melttablets, and/or mini-tablets. The dosage form can be of any shapesuitable for oral administration of a drug, such as spheroidal,cube-shaped oval, or ellipsoidal. Dosage forms can be prepared from themulti-particulates in a manner known in the art and include additionalpharmaceutically acceptable excipients, as desired.

Dosage forms may be monolithic and/or multi-unit dosage forms. Dosageforms may have a functional coating. Such coatings generally serve thepurpose of delaying the release of the drug for a predetermined period.For example, such coatings may allow the dosage form to pass through thestomach without being subjected to stomach acid or digestive juices.Thus, such coatings may dissolve or erode upon reaching a desired pointin the gastrointestinal tract, such as the upper intestine.

Such functional coatings may exhibit pH-dependent or pH-independentsolubility profiles. Those with pH-independent profiles generally erodeor dissolve away after a predetermined period, and the period isgenerally directly proportional to the thickness of the coating. Thosewith pH-dependent profiles, on the other hand, may maintain theirintegrity while in the acid pH of the stomach, but quickly erode ordissolve upon entering the more basic upper intestine.

Thus, a matrix-based, osmotic pump-based, or membrane-controlledformulation may be further coated with a functional coating that delaysthe release of the drug. For example, a membrane-controlled formulationmay be coated with an enteric coating that delays the exposure of themembrane-controlled formulation until the upper intestine is reached.Upon leaving the acidic stomach and entering the more basic intestine,the enteric coating dissolves. The membrane-controlled formulation thenis exposed to gastrointestinal fluid, and then releases baclofen, aderivative thereof or a pharmaceutically acceptable salt thereof over anextended period, in accordance with the invention. Examples offunctional coatings such as these are well known to those in the art.

Any of the oral dosage forms described herein may be provided in theform of caplets, capsules, beads, granules, particles for suspensionprior to dosing, sachets, or tablets. When the dosage form is in theform of tablets, the tablets may be disintegrating tablets, fastdissolving tablets, effervescent tablets, fast melt tablets, and/ormini-tablets. The dosage form can be of any shape suitable for oraladministration of a drug, such as spheroidal, cube-shaped oval, orellipsoidal.

Pharmaceutical compositions and dosage forms described herein mayfurther comprise at least one additional active ingredient other thanbaclofen, a derivative thereof, or a pharmaceutically acceptable saltthereof that may or may not have the same pharmaceutical effect. Suchcompounds may be included to treat, prevent, and/or manage the samecondition being treated, prevented, and/or managed with baclofen, aderivative thereof, or a pharmaceutically acceptable salt thereof, or adifferent one. Alternatively, such additional pharmaceutical compoundsmay be provided in a separate formulation and co-administered to asubject or patient with the baclofen, a derivative thereof, or apharmaceutically acceptable salt thereof composition according to thepresent disclosure. Such separate formulations may be administeredbefore, after, or simultaneously with the administration of baclofen, aderivative thereof or a pharmaceutically acceptable salt thereofcompositions.

The compositions described above can be used in methods for treating,preventing, and/or managing various diseases and/or conditions,comprising administering to a subject or patient in need thereof atherapeutically effective amount of the active ingredient, a derivativethereof, or a pharmaceutically acceptable salt thereof.

The phrase “therapeutically effective amount” refers to the amount ofthe active ingredient, derivative thereof, or a pharmaceuticallyacceptable salt thereof, which alone or in combination with one or moreother active ingredients, provides any therapeutic benefit in theprevention, treatment, and/or management of a particular diseases and/orcondition.

Baclofen is a 4-amino-3-substituted-butanoic acid derivative and astructural analog of the inhibitory neurotransmitter gamma-aminobutyricacid (GABA), and may exert its effects by stimulation of the GABA_(B)receptor subtype. Baclofen is a skeletal muscle relaxant and antispasticagent. Baclofen is useful for the alleviation of signs and symptoms ofspasticity resulting from multiple sclerosis, particularly for therelief of flexor spasms and concomitant pain, clonus, and muscularrigidity. Baclofen may also be used for the treatment of spasticityand/or other conditions related to Cerebral Palsy, Stroke, TraumaticBrain Injury, Spinal Cord Injury, and Spinal Cord Diseases. In strokepatients, baclofen should be used with caution; in some patients,baclofen has not significantly benefited stroke patients, and in others,it is not well tolerated. Baclofen has also been used as a withdrawaltreatment for patients that are resistant to, or otherwise cannot take,benzodiazepines. The inventors contemplate that a baclofen formulationsaccording to the invention may be used for any indication for whichbaclofen is approved.

The amount of the dose of the active ingredient administered, as well asthe dose frequency, will vary depending on the particular dosage formused and route of administration. The amount and frequency ofadministration will also vary according to the age, body weight, andresponse of the individual subject or patient. Typical dosing regimenscan readily be determined by a competent physician without undueexperimentation. It is also noted that the clinician or treatingphysician will know how and when to interrupt, adjust, or terminatetherapy in conjunction with individual subject or patient response.

In general, the total daily dosage for treating, preventing, and/ormanaging the conditions associated with spasticity with any of theformulations according to the present disclosure is from about 1 mg toabout 500 mg, or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 250, 300, 350, 400, 450,or 500, mg, or any number in between, of baclofen, a derivative thereof,or a pharmaceutically acceptable salt thereof. Other indications mayrequire higher doses, such as 600, 700, 800, 900, or even 1000 mg. Forexample, for an orally administered dosage form, the total daily dosemay range from about 10 mg to about 100 mg, or from about 20 mg to about90 mg, or from about 30 mg to about 80 mg, or from about 40 mg to about70 mg. Accordingly, a single oral dose may be formulated to containabout 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100,120, 140, 150, 160, 180, or 200, mg, or any number in between, ofbaclofen, a derivative thereof or a pharmaceutically acceptable saltthereof. The pharmaceutical compositions containing baclofen, aderivative thereof or a pharmaceutically acceptable salt thereof may beadministered in single or divided doses 1, 2, 3, 4, or more times eachday. Alternatively, the dose may be delivered once every 2, 3, 4, 5, ormore days. In one embodiment, the pharmaceutical compositions areadministered once per day.

As used herein, the term “prevent” or “prevention” in the context oftreatment, for example, as in “preventing spasticity” or “prevention ofspasticity” refers to a reduction in the spasticity. Prevention does notrequire 100% elimination of the symptom.

Embodiments of the invention include pharmaceutical formulationscomprising: an effective amount of 4-amino-3-(4-chlorophenyl)butanoicacid) (baclofen), and one or more pharmaceutically acceptableexcipients; wherein the formulation is a mutiparticulate formulation;and wherein on administration to a patient produces3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in thepatient; wherein a ratio C_(max(baclofen)):C_(max(M1)) is A, andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) is B; and wherein administeringthe pharmaceutical formulation to the patient produces A and B valuesthat are within 10% of a ratio C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tablet formulationaccording to Baclofen Tablets monograph as defined by US Pharmacopeiaand containing an equal amount of baclofen. In embodiments the valuesmay be within, for example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of thereference baclofen tablet formulation. In embodiments, the ratio may bethe same.

Embodiments also include methods of treating spasticity in a patientcomprising: administering to the patient a pharmaceutical formulationcomprising: an effective amount of 4-amino-3-(4-chlorophenyl)butanoicacid) (baclofen), and one or more pharmaceutically acceptableexcipients; wherein the formulation is a mutiparticulate formulation;and wherein on administration to a patient produces3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in thepatient; wherein a ratio C_(max(baclofen)):C_(max(M1)) is A, andAUC_((0-t)(baclofen)):AUC_((0-t) (M1)) is B; and wherein administeringthe pharmaceutical formulation to the patient produces A and B valuesthat are within 10% of a ratio C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tablet formulationaccording to Baclofen Tablets monograph as defined by US Pharmacopeiaand containing an equal amount of baclofen. In embodiments the valuesmay be within, for example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of thereference baclofen tablet formulation. In embodiments, the ratio may bethe same.

In embodiments, administering the pharmaceutical formulation to thepatient produces A and B values that are greater than the ratioC_(max(baclofen)):C_(max(M1)) and AUC_((0-t)(baclofen)):AUC_((0-t) (M1))for a baclofen tablet formulation according to Baclofen Tablets asdefined by US Pharmacopeia monograph. In other embodiments,administering the pharmaceutical formulation to the patient produces Aand B values that are less than the ratio C_(max(baclofen)):C_(max(M1))and AUC_((0-t)(baclofen)):AUC_((0-t)(M1)) for a baclofen tabletformulation according to Baclofen Tablets as defined by US Pharmacopeiamonograph.

In embodiments, administering a 20-mg dose of the pharmaceuticalformulation to the patient produces a C_((max)(baclofen)) value of fromabout 274 ng/mL to about 433 ng/mL. In embodiments, administering a20-mg dose of the pharmaceutical formulation to the patient produces aC_((max)(M1)) value of from about 37 ng/mL to about 75 ng/mL. Inembodiments, administering a 20-mg dose of the pharmaceuticalformulation to the patient produces a ratioC_(max(baclofen)):C_(max(M1)) of from about 4 to about 11, such as fromabout 6.1 to about 7.5, or from about 6.2 to about 6.4.

In embodiments, administering a 20-mg dose of the pharmaceuticalformulation to the patient produces a AUC_((0-t)(baclofen)) value offrom about 1707 h ng/mL to about 2896 h ng/mL. In embodiments,administering a 20-mg dose of the pharmaceutical formulation to thepatient produces a AUC_((0-t)(M1)) value of from about 461 hng/mL toabout 1017 h.ng/mL. In embodiments, administering a 20-mg dose of thepharmaceutical formulation to the patient produces a ratioAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) of from about 2 to about 5, suchas from about 2.8 to about 3.4, or from about 3.0 to about 3.2.

In embodiments, the method provides for treating spasticity resultingfrom multiple sclerosis. In embodiments, the method provides fortreating spasticity associated with at least one of flexor spasms, pain,clonus, and muscular rigidity. In embodiments, the effective amount ofbaclofen is from about 5 mg to about 20 mg, and can be administered individed or single doses, such as four 5-mg doses taken together, two10-mg doses taken together, one 20-mg dose, a divided 40-mg dose, etc.Embodiments include, for example, gradually increasing the dosingregimen where 5 mg to 20 mg dosing is taken more than once per day, suchas for example, three times a day. For example, embodiments includeadministering the baclofen as a 5-mg dose three times daily for threedays; then increasing to 10 mg three times daily for three days; thenincreasing to 20 mg three times daily for three days. Additionalincreases may be necessary up to the maximum recommended dosage.Obviously, qualified medical practitioners can modify this regimen asnecessary, including by increasing or decreasing the daily frequency, orincreasing or decreasing the number of days at each dose, etc.

Embodiments also include methods of controlling exposure to baclofenmetabolite 3-(4-chlorophenyl)-4-hydroxybutyric acid in a patientcomprising: administering to the patient a pharmaceutical formulationcomprising an effective amount of 4-amino-3-(4-chlorophenyl)butanoicacid) (baclofen), and one or more pharmaceutically acceptableexcipients; wherein the formulation is a mutiparticulate formulation;and wherein on administration to a patient produces3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in thepatient; and wherein the coefficient of variation for AUC_((0-t)(M1)) is0.34 or less. In embodiments, the coefficient of variation forAUC_((0-t)(M1)) is 0.30 or less, such as 0.29, 0.28, 0.27, 0.26, 0.25,0.24, 0.23, 0.22, 0.21, 0.20, or less.

Embodiments include methods of administering baclofen granule with orwithout water (or other liquids), and with or without soft foods. Theinventors do not believe that administering with soft food or watersignificantly affects the pharmacokinetics of baclofen or the M1metabolite when the baclofen is administered as a granule formulation asdescribed herein. If necessary to assist administration or patientcompliance, granules can easily be mixed with soft food. Granuleformulations further allow for easy administration to patients who areunable to self-administer. For example, granule formulations may beadministered through a feeding tube with liquids (such as a nasogastrictube, percutaneous endoscopic gastronomy tube, or gastrojejunostomytube).

Note, however, that administration of a baclofen granule formulation asdescribed herein with a high fat meal (as defined by FDA and detailedbelow) is expected to reduce the rate of absorption of the baclofen (asreflected by C_(max), as well as the C_(max) for the metabolite M1). Theextent of absorption (as reflected by AUC values) is affected somewhatby administration with a high fat meal, but to a less extent than therate of absorption. Example 9 below provides details of these findings.

EXAMPLES

The inventors assessed the stabilizing effects ofpoly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate (EUDRAGIT™ E PO, Evonik) on baclofen, gabapentin, andpregabalin in various compositions and manufacturing processes comparedto the stabilizing effects of the a-amino acids used as stabilizers inU.S. Pat. No. 7,309,719.

Example 1 Accelerated Stability Studies

Baclofen formulations were prepared with pure API and a stabilizerselected from EUDRAGIT™ E PO (“PO” refers to powder; “EPO” used hereinrefers to EUDRAGIT™ E PO), glycine, L-leucine, and L-isoleucine in 1, 5,and 10% (m/m) concentrations or without any further ingredients, asprovided in Table 1 below. Preparations were manufactured as:

-   dry powder blends treated in a mortar (T),-   dry powder blends compacted in a tablet press punching tool ((K): 10    mm, round, no notch),-   wet blends with ethanol (E), and-   wet blends with water (W).

TABLE 1 Test batch Material Amount [g] 1 Baclofen 60.000 T/K/E/W — — 2Baclofen 59.400 T/K/E/W EUDRAGIT ™ E PO 0.600 3 Baclofen 57.000 T/K/E/WEUDRAGIT ™ E PO 3.000 4 Baclofen 54.000 T/K/E/W EUDRAGIT ™ E PO 6.000 5Baclofen 59.400 T/K/E/W Glycine 0.600 6 Baclofen 57.000 T/K/E/W Glycine3.000 7 Baclofen 54.000 T/K/E/W Glycine 6.000 8 Baclofen 59.400 T/K/E/WL-Leucine 0.600 9 Baclofen 57.000 T/K/E/W L-Leucine 3.000 10  Baclofen54.000 T/K/E/W L-Leucine 6.000 11  Baclofen 59.400 T/K/E/W L-Isoleucine0.600 12  Baclofen 57.000 T/K/E/W L-Isoleucine 3.000 13  Baclofen 54.000T/K/E/W L-Isoleucine 6.000 Ethanol each E* 4.000 Water purif. each W*4.000

Preparations were stored at 60° C. in closed glass vials. Samples weretaken initially, after 1 week, and after 3 weeks. The samples weretested for impurity A (lactam) and unknown organic impurities by meansof HPLC. The results are shown in FIGS. 1-4 . (For baclofen, impurity Ais 4-CPP.)

Gabapentin formulations and pregabalin formulations were also preparedwith the same ratios of API to stabilizer described in Table 1 forbaclofen. The preparations were stored in closed glass vials at 60° C.for gabapentin and at 80° C. for pregabalin. The content of lactamimpurity A and unknown organic impurities for all three molecules wasanalyzed initially and after storage for defined periods by means ofHPLC. These results are shown in FIGS. 5-12 .

FIGS. 1-12 show that a stabilized and free-flowable pharmaceuticalformulation can be obtained by several manufacturing processes,including dry compaction and wet granulation, of baclofen, gabapentin,and pregabalin with EUDRAGIT™ E. However, unexpectedly, only baclofen isstabilized by EUDRAGIT™ E.

Note that these experiments were performed with very large amounts ofdrug as compared to the stabilizer, so as to amplify the ability toobserve lactam formation. Even though stabilization is observed atrelatively low stabilizer:active ratios, the inventors contemplate usinghigher stabilizer:active ratios to maximize the stabilizing effect.

The accelerated stability data indicates that EUDRAGIT™ E stabilizationis specific to baclofen alone. Based on the data gathered on thestructurally similar molecules gabapentin and pregabalin, EUDRAGIT™ Ewas observed to have the opposite effect with formation of lactamimpurity A being accelerated. In summary, EUDRAGIT™ E was observed tohave a stabilization effect on baclofen and a destabilization effect ongabapentin and pregabalin.

Example 2 Infrared Spectroscopy to Assess Stabilization Mechanism on4-amino-3-Substituted-Butanoic Acid Derivatives by EUDRAGIT™ E

To better elucidate the mechanistic understanding of EUDRAGIT™ E and theresultant stabilization effect with Baclofen, several mixtures wereprepared as outlined below in Table 2. The %w/w concentration ofEUDRAGIT™ E to Baclofen was altered to enable spectroscopicidentification of any potential interaction.

TABLE 2 Baclofen to Ratio EUDRAGIT ™ E PO EPO:Baclofen (% w/w) (w/wbasis) 10%  9:1 15% 5.7:1 20%  4:1 40% 1.5:1 60% ~0.7:1 

Infrared spectroscopy was performed on the mixtures outlined in Table 3to assess any spectroscopic shift that occurred in comparison toEUDRAGIT™ E and Baclofen alone. The spectroscopic data shown in FIGS.13-15 reveal that an EUDRAGIT™ E dependent shift of Baclofen (vibrationC═O) from 1530 cm⁻¹to 1525 cm⁻¹ and a lowered signal at 1490 cm⁻¹, whichis indicative of a direct, stabilizing interaction of EPO amino groupand the carboxylic group of baclofen. In contrast to baclofen, there wasno observed EUDRAGIT™ E dependent shift in the 1400 to 1800 cm⁻¹ rangeof the spectrum, indicating that there was no direct interaction withEUDRAGIT™ E with gabapentin and pregabalin, as shown in FIG. 16 .

Example 3 Formation of Baclofen Granules

Initial studies were performed to determine whether the API, baclofen,should be micronized for the granule formulations. Based on thepre-selection of excipients, three formulations (baclofen micronized,non- micronized and placebo) were prepared by mortar granulation withethanol as granulation fluid. A switch to an ethanol-based granulationfluid was made with the aim to reduce drying time and thereby increasestability. Furthermore, hydrate formation of baclofen was assumed toimpair dissolution. The composition of the granules is outlined in thetable below.

Granule Batch: Granule - Granule -- Material non-micronized micronizedBaclofen (non- micronized) 10 — Baclofen (micronized) — 10 MCC 101 450450 Pharmacoat 606 15 15 Crospovidone 25 25 Ethanol* 58.2 58.2 Water*1.8 1.8 mg/SD 500 500

The preparations with different API grades (non-micronized andmicronized) were used for characterization of dissolution profile (FIG.19 ). A placebo was used as background for the implementation of thedissolution method (data not shown).

Differences in the dissolution and release profiles were observed (FIG.19 ). The dissolution rate of the marketed oral tablet formulation (madeby ratiopharm) was superior to pure non-micronized API and inferior tomicronized API, as well as inferior to both granules (micronized andnon-micronized). The dissolution of both granules was comparablesupporting that the particle size of the drug substance once ingranulated form, is not critical to the release profile of the dosageform. Accordingly, further compositions were made with a micronizedbaclofen.

Granules were manufactured with a Zanchetta Roto P50 on a 8.79 kg scale(10.000 single doses). Baclofen and excipients were sieved through 1.0mm, loaded into the granulator and dry blended for 10 min. Ethanol 96%was then sprayed onto the powder bed at a constant spraying pressure of2 bar. Subsequently, the tip speed was increased and the wet mixture wasmassed for 10 min. The wet mixture was centered in the granulator andthe granulator jacket was heated up to 60° C. The granules were driedunder vacuum while tilting the granulator bowl and occasional stirring(every 500 sec for 10 sec at 80 rpm) for about 100 min. Afterdischarging, the granules were dry sieved through 1.0 mm. Formula issummarized in Table 3. Particle size distribution by sieve analysis ofthe baclofen granule batches is shown in FIG. 17 .

TABLE 3 Batch 1 Batch 2 Single doses (SD) 10000 10000 Material (Error!Reference source not found. [mg/SD] [mg/SD] and Error! Reference sourcenot found.) Baclofen (micronized MCKO) — 20.00 Mannitol 332.00 332.00Xylitol 420.00 400.00 Saccharin sodium 1.00 1.00 Hypromellose 60.0060.00 Amino Methacrylate Copolymer 36.00 36.00 Crospovidone 30.00 30.00Alcohol (removed during operation) 200.00 200.00 Granules [mg/SD] 879.00879.00

Example 4 Formation of Final Blends

Placebo granules and API granules were processed to final blends.Colloidal silicon dioxide was sieved with a part of the placebo granules(or verum for the 20 mg formulation) through 1.0 mm. Strawberry flavor,calcium stearate, and talc were sieved separately (1.0 mm). Blending wasperformed via a Turbula mixer. Blending times and particularities aregiven in Table 4. FIG. 18 shows the particle size distribution by sieveanalysis of the baclofen final blends.

TABLE 4 Final blend batch 1 2 3 SD 6000 5000 3000 Dosage strength[mg/SD] 5 10 20 Material [mg/SD] [mg/SD] [mg/SD] Baclofen granules219.75 439.50 879.00 Placebo granules 659.25 439.50 — Colloidal silicondioxide 2.00 2.00 2.00 Calcium stearate 5.00 5.00 5.00 Talc 8.00 8.008.00 Flavor strawberry 6.00 6.00 6.00 Final blend [mg/SD] 900.00 900.00900.00

Example 5 Filling of Stick Packs

Stick packs were filled with the previously manufactured final blends asdescribed in Table 5, using a SBL-50 MERZ stick pack filling machine anda PET12/ALU9/PE50 43x80mm stick pack foil. All blends were fillable withvery low deviations of the filling mass given as standard deviation andmaximum deviation. Baclofen content was uniform in all three batches asshown in Table 6.

TABLE 5 Granules Final blend Stick packs X Y Z mg/SD   5 10 20 API grademicronized micronized micronized Stick pack foil PET12/ALU9/PE50PET12/ALU9/PE50 PET12/ALU9/PE50 43 × 80 mm 43 × 80 mm 43 × 80 mm T(transversal 135/140 sealing) [° C.] (left/right) T (longitudinal130/130 sealing) [° C.] (front/back) Filling cycle 40 [min⁻¹] T (room)[° C.] 20-21 20-21 21-22 rH (room) [%] 34-40 33-36 31 Number of Sticks5000 4000  3500  produced SD (max weight 0.5-1.2 0.4-1.0 0.4-0.6deviation) [%] (2.1) (2.0) (1.2)

TABLE 6 Granules Final blend Stick packs X Y Z mg/SD 5 10 20 API grademicronized micronized micronized X= 98.521 98.035 98.568 s= 2.072 1.6110.889 AV= 4.973 4.331 2.132

Example 6 Simulated Long-Term Stability Testing

Reliable estimates for ambient shelf-life values can be achieved inrelatively short times by combining an experimental design thatdecouples temperature and relative humidity (RH) effects with anisoconversion paradigm¹. The Accelerated Stability Assessment Program(ASAP) was conducted with two test batches P and Q having EPO:baclofenratios of 3.6:1 (conditions described in

¹ Waterman AAPS PharmSciTech, Vol. 12, No. 3, 2011

TABLE 7 Study conditions and test schedule of ASAP Time Condition PointsStorage Container 50° C./75% RH 4 d, 14 d Open glass bottle stored indesiccators that is loaded with an aqueous NaCl slurry 60° C./5% RH 7 d,14 d Open glass bottle stored in desiccators that is loaded with anaqueous LiBr slurry 60° C./45% RH 4 d, 7 d Open glass bottle stored indesiccators that is loaded with an aqueous K₂CO₃ slurry 70° C./5% RH 4d, 14 d Open glass bottle stored in desiccators that is loaded with anaqueous LiBr slurry 70° C./75% RH 8 h, 4 d Open glass bottle stored indesiccators that is loaded with an aqueous NaCl slurry 80° C./45% RH 8h, 24 h Open glass bottle stored in desiccators that is loaded with anaqueous K₂CO₃ slurry

Solid API and drug product chemical stability is affected by the RH thatthe sample experiences. The moisture modified Arrhenius equation(Equation 1) quantifies drug product stability as a function oftemperature and humidity:

$\begin{matrix}{{\ln k} = {{\ln A} - \frac{Ea}{RT} + {B({RH})}}} & {{Equation}1:{moisture}{modified}{Arrhenius}{equation}}\end{matrix}$

where k is the degradation rate (typically percent degradant generatedper day), A is the Arrhenius collision frequency, Ea is the energy ofactivation for the chemical reaction, R is the gas constant (1.986cal/(mol K)), T is the temperature in Kelvin, and B is a humiditysensitivity constant which has been found to vary from 0 to 0.10. Theform of Equation 1 indicates that chemical instability increasesexponentially with an increase in RH. RH can have a very significanteffect on chemical stability, depending on the B-term.

Using the modified Arrhenius equation the achieved data are evaluatedand the terms k, Ea, and B are determined. For each temperature/relativehumidity condition, the reaction rate k and the activation energy Ea areestimated from the slopes of the degradation rate (k) vs. time (t) lineand ln(k) vs.1/T. The constant B is determined as the slope of the In(k) vs. RH straight line.

Test batches P and Q were stressed as described in 7. Peak areas ofBaclofen, 4-CPP, and the sum of all impurities before and afterstressing are given as % for P

and Q

. With the results at different time points, the degradation rates werecalculated. Via Equation 1, rate constants (k) were calculated fordifferent temperatures and relative humidities

. The shelf life at conditions for long term stability (25° C. and 60%RH) was predicted on the base of the mean activation energy (Ea) and aworst case scenario

. Even in the worst case, formation of 4% of 4-CPP (limit for Baclofentablets in the USP) would need over 40 years. To ensure that even higherdemands could be satisfied, the calculation was adapted for anacceptance value of 4-CPP at 0.5%, where a shelf life of 5.1 years waspredicted in the worst case for batch P and 7.5 years for batch Q.

TABLE 8 Assay and purity of stored samples of batch P at differentstorage conditions and time points for ASAP Baclofen 4-CPP RT 10.69 5.67RRT Batch P 1.00 0.53 sum of imp. sum 1 initial 99.93 0.00 0.07 100.00 2initial 99.94 0.00 0.07 100.01 1 8 h@70° C./75% r.F 99.44 0.39 0.56100.00 2 8 h@70° C./75% r.F 99.47 0.38 0.53 100.00 1 8 h@80° C./45% r.F98.97 0.67 1.04 100.01 2 8 h@80° C./45% r.F 98.96 0.66 1.05 100.01 1 24h@80° C./45% r.F 97.21 2.13 2.79 100.00 2 24 h@80° C./45% r.F 97.29 2.062.71 100.00 1 4 d@50° C./75% r.F 99.75 0.14 0.25 100.00 2 4 d@50° C./75%r.F 99.77 0.12 0.23 100.00 1 4 d@60° C./45% r.F 99.41 0.22 0.60 100.01 24 d@60° C./45% r.F 99.35 0.33 0.65 100.00 1 4 d@70° C./75% r.F 97.262.24 2.74 100.00 2 4 d@70° C./75% r.F 97.27 2.28 2.74 100.01 1 7 d@60°C./5% r.F 99.63 0.20 0.37 100.00 2 7 d@60° C./5% r.F 99.64 0.20 0.36100.00 1 7 d@60° C./45% r.F 99.22 0.39 0.80 100.02 2 7 d@60° C./45% r.F99.20 0.36 0.80 100.00 1 14 d@60° C./5% r.F 99.35 0.36 0.66 100.01 2 14d@60° C./5% r.F 99.39 0.33 0.61 100.00 1 14 d@50° C./75% r.F 99.33 0.390.67 100.00 2 14 d@50° C./75% r.F 99.30 0.40 0.71 100.01 1 14 d@70°C./5% r.F 98.03 1.59 1.98 100.01 2 14 d@70° C./5% r.F 98.05 1.56 1.9499.99

TABLE 9 Assay and purity of stored samples of batch Q at differentstorage conditions and time points for ASAP Baclofen 4-CPP RT 10.69 5.67RRT Batch Q 1.00 0.53 sum of imp. sum 1 initial 99.92 0.00 0.08 100.00 2initial 99.93 0.00 0.07 100.00 1 8 h@70° C./75% r.F 99.71 0.23 0.30100.01 2 8 h@70° C./75% r.F 99.70 0.23 0.30 100.00 1 8 h@80° C./45% r.F99.47 0.43 0.53 100.00 2 8 h@80° C./45% r.F 99.47 0.42 0.53 100.00 1 24h@80° C./45% r.F 98.06 1.45 1.95 100.01 2 24 h@80° C./45% r.F 98.02 1.491.98 100.00 1 4 d@50° C./75% r.F 99.76 0.09 0.25 100.01 2 4 d@50° C./75%r.F 99.77 0.08 0.24 100.01 1 4 d@60° C./45% r.F 99.69 0.14 0.31 100.00 24 d@60° C./45% r.F 99.74 0.14 0.25 99.99 1 4 d@70° C./75% r.F 98.10 1.441.90 100.00 2 4 d@70° C./75% r.F 98.09 1.52 1.92 100.01 1 7 d@60° C./5%r.F 99.78 0.12 0.22 100.00 2 7 d@60° C./5% r.F 99.77 0.13 0.23 100.00 17 d@60° C./45% r.F 99.63 0.27 0.37 100.00 2 7 d@60° C./45% r.F 99.660.26 0.35 100.01 1 14 d@60° C./5% r.F 99.48 0.28 0.53 100.01 2 14 d@60°C./5% r.F 99.45 0.30 0.57 100.02 1 14 d@50° C./75% r.F 99.50 0.23 0.4999.99 2 14 d@50° C./75% r.F 99.49 0.27 0.50 99.99 1 14 d@70° C./5% r.F97.86 1.84 2.15 100.01 2 14 d@70° C./5% r.F 97.71 1.98 2.30 100.01

TABLE 10 Rate constants (k) for 4-CPP formation at differenttemperatures and different RH Temperature [° C.] 50 60 70 80 Batch P  5%RH — 0.02 0.11 — 45% RH — 0.05 — 2.09 75% RH 0.03 — 0.54 — Batch Q  5%RH — 0.02 0.14 — 45% RH — 0.04 — 1.47 75% RH 0.02 — 0.36 —

TABLE 11 Predicted shelf life at 25° C. and 60% RH of batch P and batchQ with the mean calculated activation energy (Ea) and in the worst caseBatch P Batch Q Stability condition Predicted shelf life 25/60 [Years]Predicted shelf life 25/60 [Years] T[° C.]/RH[%] 4-CPP = 0.5% 4-CPP = 4%4-CPP = 0.5% 4-CPP = 4% 50/75 (Mean Ea) 8.5 67.8 17.5 139.9 50/75 (Worstcase) 5.1 40.8 7.5 60.2

Example 7 Real Long-Term Testing

To further demonstrate the effectiveness of the present invention inensuring baclofen stability, six-month stability testing was performedunder accelerated aging conditions (40° C., 75% RH).

TABLE 12 Baclofen granules (5 mg) Batch No.: X1 Packaging material: PET12/ALU 9/PE 50 stick pack foil (43 × 80 mm) 40° C./75% rh Period ofstorage Initial 1 month 3 months 6 months Test Acceptance criteriaResults Content of 90.0-110.0% of 99.2% 99.4% 99.6% 98.4% baclofen byHPLC nominal content Degradation products by HPLC 4-CPP n.m.t. 4.0%<0.05% <0.05% 0.06% 0.13% unknown impurity n.m.t. 0.2% 0.06% (RRT =0.94) <0.05% <0.05% <0.05% total unknown n.m.t. 1.0% 0.06% <0.05% <0.05%<0.05% impurities total of all n.m.t. 5.0% 0.06% <0.05% 0.06% 0.13%impurities

TABLE 13 Baclofen granules (10 mg) Batch No.: X2 Packaging material: PET12/ALU 9/PE 50 stick pack foil (43 × 80 mm) 40° C./75% rh Period ofstorage Initial 1 months 3 months 6 months Test Acceptance criteriaResults Content of 90.0-110.0% of 98.2% 97.7% 98.0% 98.1% baclofen byHPLC nominal content Degradation products by HPLC 4-CPP n.m.t. 4.0%<0.05% <0.05% 0.06% 0.14% unknown impurity n.m.t. 0.2% <0.05% <0.05%<0.05% 0.06% (RRT = 0.40) total unknown n.m.t. 1.0% <0.05% <0.05% <0.05%0.06% impurities total of all n.m.t. 5.0% <0.05% <0.05% 0.06% 0.20%impurities

TABLE 14 Baclofen granules (20 mg) Batch No.: X3 Packaging material: PET12/ALU 9/PE 50 stick pack foil (43 × 80 mm) 40° C./75% rh Period ofstorage Initial 1 months 3 months 6 months Test Acceptance criteriaResults Content of 90.0-110.0% of 98.0% 99.1% 97.0% 96.7% baclofen byHPLC nominal content Degradation products by HPLC 4-CPP n.m.t. 4.0%<0.05% <0.05% 0.07% 0.14% unknown impurity n.m.t. 0.2% <0.05% 0.08% (RRT= 0.67) <0.05% <0.05% total unknown n.m.t. 1.0% <0.05% 0.08% <0.05%<0.05% impurities total of all n.m.t. 5.0% <0.05% 0.08% 0.07% 0.14%impurities

As can be seen from Tables 12-14 above, the stabilized baclofenformulations of the present invention have less than 0.2% of 4-CPP, evenafter six months of accelerated stability testing. That thisstabilization occurred with baclofen, but not with related drugsgabapentin and pregabalin, is quite surprising. It is also commerciallyimportant and significant in that it solves a problem that has longexisted with baclofen.

Example 8 Pharmacokinetic Studies

This study was designed to characterize the pharmacokinetics (PK) of thegranule formulation of baclofen relative to that of an oral tablet form,both dosed at 20 mg. As the granule dosage form is designed to be takeneither with or without water, or could be mixed in soft foods, the studywas designed to compare the PK across each administration type (with orwithout water or in soft foods), as compared to an established oral doseof baclofen tablets 20 mg in a fasted state. This study was alsodesigned to understand the proportionality equivalence between four (4)sachets (or ‘stickpacks’) of 5 mg baclofen granules (20 mg dose total)to that of the single oral dose of baclofen tablets (20 mg). All datawas generated using a validated bioanalytical method for Baclofen andits predominant metabolite Ml: Baclofen3-(4-chlorophenyl)-4-hydroxybutyric acid.

This was an open-label, randomized, five-way crossover, single-dosestudy comparing the pharmacokinetics (PK) of baclofen administered as anoral granule 20 mg presentation (whether with or without water or insoft foods) relative to that of a 20 mg oral baclofen tablet referencedose under fasting conditions. A total of 30 healthy, adult male and/orfemale smokers (no more than 25 cigarettes per day) and non-smokersubjects were planned to be included in this study and an estimatedtotal of at least 26 healthy subjects were expected to complete thestudy. Prior to entering the trial, subjects had a screening visit toestablish eligibility within 28 days before study drug administration.Subjects were randomized to receive a single dose (20 mg) of baclofen ina crossover approach to receive each of Treatments A, B, C, D, and E inPeriods 1 to 5 of the study as follows:

-   Treatment A: Baclofen tablets 20 mg;-   Treatment B: Baclofen granules 20 mg, without water;-   Treatment C: Baclofen granules 20 mg, with water;-   Treatment D: Baclofen granules 20 mg, in soft food;-   Treatment E: Baclofen granules 20 mg, with water, provided as 4    sachets of 5 mg each.

Subjects eligible for the study were admitted to the clinic in theevening of Study Day −1, to begin a fast of at least 10 hours prior tothe first study drug treatment. The single dose of assigned baclofenform was followed by a series of blood draws for PK analysis: atpre-dose, 15, 30 and 45 minutes and at 1.00, 1.50, 2.00, 2.50, 3.00,4.00, 6.00, 8.00, 10.0, 12.0, 24.0, and 48.0 hours post dosing. Subjectswere released from the clinic after the 24-hour blood draw.

Following a 7-day washout interval, all subjects returned to the clinicfor Period 2, during which they continued with the randomized assignmentof an alternate form of baclofen to that consumed in the previousperiod, followed by collection of the same set of blood samples over 48hours. The same process was repeated through all 5 periods, after whicheach subject had received a single dose of each of the forms of baclofenidentified above, followed by the same set of blood samples collectedover 48 hours, the local tolerability assessment, and the tasteacceptability assessment (granule forms only). All subjects remained atthe clinic site for the first 24 hour duration of each treatment periodand were returned to the clinic for the 48 hours PK blood collection.

The following Table summarizes the drug products for these Treatments.

Study Drugs Treatments Parameter Treatment A B, C, and D Treatment EProduct Baclofen Baclofen Baclofen Strength 20 mg 20 mg/sachet or 5mg/stick pack ‘stick pack’ Dosage form Tablet Granules Granules Dose 20mg 20 mg 20 mg (4 stick administered packs of 5 mg each) Route of OralOral Oral administrationTreatment A: Baclofen Oral tablets 20 mg:

One 20 mg tablet/single dose was swallowed whole with 240 mL of water. Ahand and mouth check was performed to ensure consumption of themedication. Subjects were warned neither to chew nor to bite themedication.

Treatment B: Baclofen granules 20 mg, without water:

One stick pack of 20 mg baclofen granules administered directly into themouth (was dissolved in the mouth). Subjects were warned neither to chewnor to bite the medication. A mouth check was performed approximately 1minute after study drug administration to ensure consumption of themedication.

Treatment C: Baclofen granules 20 mg, with water:

One stick pack of 20 mg baclofen granules administered directly into themouth, followed with 240 mL water. Subjects were warned neither to chewnor to bite the medication. A mouth check was performed to ensureconsumption of the medication.

Treatment D: Baclofen granules 20 mg, in soft food:

One stick pack of 20 mg baclofen granules, sprinkled into 1 tablespoonof applesauce and swallowed, followed by 240 mL of water, given underfasting conditions. Subjects were warned neither to chew nor to bite themedication. A mouth check was performed to ensure consumption of themedication.

Treatment E: Baclofen granules 20 mg, provided as 4 stick packs of 5mgeach:

Four stick packs of 5 mg baclofen granules administered directly intothe mouth with 240 mL of water. The start of dosing was set to the timeof administration of the first pack of baclofen, and the complete dosingprocedure did not exceed 2 minutes. Subjects were warned neither to chewnor to bite the medication. A mouth check was performed to ensureconsumption of the medication.

Food and Fluid Intake

Subjects were fasted for 4 hours prior to the Screening Visit (i.e.,refrain from eating or drinking, with the exception of water). Subjectswere also refrained from eating or drinking (with the exception ofwater) for at least 10 hours prior to each administration of study drug.Additionally, with the exception of 240 mL of water provided at the timeof study drug administration, water was prohibited from 1 hour prior toand 1 hour post study drug administration. Lunch was providedapproximately 4.5 hours after study drug administration, and dinner wasprovided approximately 10 hours after the first dose of study drug.Additionally, a light evening snack was allowed approximately 3.5 hoursafter dinner. Following the single dose in each Period, subjects wereprovided a standardized diet that was similar in composition during eachtreatment period.

Drug Concentration Measurements Sample Collection and Processing

A dead-volume intravenous catheter was used to subjects for bloodcollection to avoid multiple skin punctures. Otherwise, blood sampleswere collected by direct venipuncture. The total volume of blood drawnfrom each subject completing this study did not exceed 326 mL.

Blood Samples:

In each period, a total of 16 blood samples were drawn from each subjectfor determination of baclofen concentrations. All blood samples weredrawn into blood collection tubes (1 x 3 mL) containing dipotassiumethylenediaminetetraacetic acid (K₂EDTA). Blood samples were collectedprior to drug administration (0.000), 0.250, 0.500, 0.750 minutes, andat 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.0, 12.0, 24.0, and48.0 hours post dose in each period. The time tolerance window for bloodsamples collected during the confinement period was ±1 minute for allsamples collected before 8 hours post-dose and ±3 minutes for subsequentsamples. The time tolerance window for return visit samples was ±30minutes.

Sample collections done outside the pre-defined time windows were notconsidered as protocol deviations since actual post-dose sampling timeswere used for PK and statistical analyses. Unless otherwise specified orfor subject safety, when blood draws and other procedures coincided,blood draws had precedence.

Blood samples were cooled in an ice/water bath and were centrifuged at2000±20 g for at least 10 minutes at approximately 4° C. (no more than240 minutes passed between the time of each blood draw and the start ofcentrifugation). Two (2) aliquots of at least 0.5 mL (when possible) ofplasma were dispensed into polypropylene tubes as soon as possible. Thealiquots were transferred to a -80° C. freezer (no more than 180 minutespassed between the start of centrifugation and aliquot storage), pendinganalysis/shipment to the analytical facility.

Pharmacokinetic Analyses Handling of the Below the Lower Limit ofQuantitation (BLQ) and the No Reportable Concentration Values

During PK and statistical analyses, drug concentrations BLQ of an assaywas considered as zero except when they occur between two non-BLQconcentrations where they were considered as missing. A sample with a noreportable value occurring prior to the dosing for a given period wasreplaced by zero. For tabulation, graphical representation andcalculation purposes, all samples with no reportable value observedafter dosing was set to missing.

Handling of the Difference Between the Scheduled and the Actual SamplingTimes

The actual clock time for dosing and the actual clock time for eachcollection time for the PK samples were recorded using the electronicdata capture. For all sampling times, the actual sampling times werecalculated as the difference between the sample collection actual clocktime and the actual clock time of dosing. The actual post-dose samplingtimes expressed in hours and rounded off to three decimal digits wereused to calculate the PK parameters, except for pre-dose samplesoccurring prior to dosing, which was always reported as zero (0.000),regardless of the time difference. In the PK section of the report,scheduled sampling times were presented in concentration tables and meangraphs while actual times were presented for the individual graphs. Alisting of the actual times for PKs was provided for PK samples.

Pharmacokinetic Parameters

Plasma samples were used to calculate the following baclofen and M1 PKparameters by standard non-compartmental methods:

-   -   AUC_(0-t): Area under the time-concentration curve of plasma        baclofen or M1 from time zero until the last quantifiable value.        AUC_(0-t) was calculated using the trapezoidal method linear        interpolation.    -   AUC_(0-∞): Area under the time-concentration curve of plasma        baclofen or M1 extrapolated to infinity, calculated as        AUC_(0-t)+C_(last)/λ_(z), where C_(last) is the last measurable        concentration.    -   C_(max): Observed maximum concentration of plasma baclofen or        M1.    -   t_(max): Sampling time of observed maximum plasma concentration.    -   λ_(z): Terminal elimination rate constant.    -   t_(1/2): Terminal elimination half-life of plasma Baclofen or        M1, calculated as ln(2)/λ_(z). This parameter was the negative        of the estimated slope of the linear regression of the        log-transformed concentration (natural logarithm) versus time        profile in the terminal elimination phase. At least 3        concentration points were used in estimating λ_(z). The time        point where log-linear λ_(z) calculation begins (λ_(z Lower)),        and the actual sampling time of the last quantifiable        concentration used to estimate the λ_(z) (λ_(zl Upper)) were        reported with the correlation coefficient from the linear        regression to calculate λ_(z).

The t_(1/2) parameters were not estimated for plasma concentration-timeprofiles where the terminal linear phase was not clearly defined.

Some aspects considered (but not to be limited to) when determining dataavailability for PK population: inclusion and exclusion criteria,acceptable times for visit dates and measurements, compliance withtreatment, the nature and quality of the data, withdrawal and anyprotocol deviation. Any decision for excluding data from the final dataset was provided with a detailed explanation and was properly recordedand dated with Sponsor's approval. The final responsibility of decidingwhich subjects were to be included or excluded lies with Sponsor.

Statistical Analyses

Individual and mean plasma concentration versus time curves for eachtreatment were presented using linear and semi-log scales. Plasmaconcentrations of each analyte were listed and summarized by study drugtreatment for the Per Protocol population using descriptive statistics(number of observations, arithmetic and geometric means, SD, coefficientof variation [CV%], median, Min, and Max). C_(max) and t_(max) ofbaclofen and M1 were taken directly from the individual plasmaconcentration data. Assessments of extent and rate of absorption ofbaclofen and M1 for all baclofen treatments were based on these standardPK parameters.

Plasma PK parameters were listed and summarized by study drug treatmentfor the Per Protocol population using descriptive statistics. Arithmeticmeans, SD, Min, Max, median, Geometric mean and CV% were calculated forPK parameters. For the comparison of Baclofen granules 20 mg, withoutwater (B) versus Baclofen Tablets 20 mg (A), Baclofen granules 20 mg,with water (C) versus Baclofen Tablets 20 mg (A), Baclofen granules 20mg, in soft food (D) versus Baclofen Tablets 20 mg (A), Baclofengranules 20 mg, with water, provided as 4 sachets of 5 mg each (E)versus Baclofen Tablets 20 mg (A) , and Baclofen granules 20 mg given,with water, provided as 4 sachets of 5 mg (E) versus Baclofen granules20 mg, with water (C).

Whenever a PK parameter was calculated for only one period for asubject, the subject was excluded from the statistical analysisinvolving this parameter for the concern comparison. However, data fromthe available period was included in the descriptive statistics. If asubject had a major protocol deviation in one period, data from otherperiods would have been used in statistical analysis unless treatment Ais missing. The subjects who completed at least two study periodsincluding Treatment A was included in statistical analysis. Data fromincomplete or excluded period was not included in the descriptivestatistics and statistical analysis.

Treatment

The following table summarizes treatment groups.

Treatment Treatment Treatment Treatment Treatment A B C D E OverallNumber of Subjects Dosed 29 30 28 29 29 30 Safety Population, N (%) 29(100) 30 (100)  28 (100) 29 (100) 29 (100) 30 (100)  Pharmacokinetic 29(100) 29 (96.7) 28 (100) 29 (100) 29 (100) 29 (96.7) Population, N (%)Treatment A: Baclofen tablets 20 mg. Treatment B: Baclofen granules 20mg, without water. Treatment C: Baclofen granules 20 mg, with water.Treatment D: Baclofen granules 20 mg, in soft food. Treatment E:Baclofen granules 20 mg, with water, provided as 4 stick packs of 5 mgeach. %: Number of subjects included compared to the number of subjectsdosed.

Pharmacokinetic Analysis

The PK parameters calculated for baclofen and baclofen M1 wereAUC_(0-t), AUC_(0-∞), C_(max), t_(max), λ_(Z), and t_(1/2). The PKvalues for the Treatment Groups A-E (baclofen) are summarized in thetables below.

Summary of Pharmacokinetic Parameters of Baclofen by Treatment-PerProtocol Population Treatment A Treatment B Parameter Geo. Geo. Geo.Geo. (unit) N Mean Mean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t)29 2397.48 2350.29 484.92 20.23 20.57 29 2396.45 2348.70 499.87 20.8620.46 (h*ng/mL) AUC_(0-∞) 29 2454.57 2409.44 479.45 19.53 19.87 292443.30 2398.03 488.86 20.01 19.75 (h*ng/mL) C_(max) (ng/mL) 29 385.77378.81 73.95 19.17 19.80 29 365.46 359.06 67.79 18.55 19.65 t_(1/2) (h)29 5.44 — 0.80 14.67 — 29 5.46 — 0.84 15.43 — λ_(Z) (/h) 29 0.1300 —0.0190 14.6286 — 29 0.1299 — 0.0197 15.1980 — Parameter (unit) N MedianMin Max N Median Min Max t_(max) (h) 29 0.995 0.487 2.990 — — 29 1.4870.737 3.997 — — ¹Geometric mean and coefficient of variation (%) wereadded to the summary statistics for AUCs and C_(max) only; << — >>: NotApplicable. N: Number of observations; SD: Standard Deviation; CV:Coefficient of variation; Min: Minimum; Max: Maximum. Treatment A:Baclofen tablets 20 mg. Treatment B: Baclofen granules 20 mg, withoutwater. Treatment C: Baclofen granules 20 mg, with water. Treatment D:Baclofen granules 20 mg, in soft food. Treatment E: Baclofen granules 20mg, with water, provided as 4 stick packs of 5 mg each.

Summary of Pharmacokinetic Parameters of Baclofen by Treatment-PerProtocol Population Treatment C Treatment D Parameter Geo. Geo. Geo.Geo. (unit) N Mean Mean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t)28 2362.06 2325.41 425.92 18.03 18.19 29 2304.67 2263.37 446.28 19.3619.57 (h*ng/mL) AUC_(0-∞) 28 2407.31 2372.71 417.25 17.33 17.50 292345.11 2305.97 437.38 18.65 18.89 (h*ng/mL) C_(max) (ng/mL) 28 360.78353.87 72.40 20.07 20.36 29 363.33 358.15 59.94 16.50 17.88 t_(1/2) (h)28 5.66 — 0.91 16.03 — 29 5.87 — 1.10 18.81 — λ_(Z) (/h) 28 0.1256 —0.0206 16.3695 — 29 0.1221 — 0.0227 18.6073 — Parameter (unit) N MedianMin Max N Median Min Max t_(max) (h) 28 1.486 0.488 2.987 — — 29 1.4880.488 3.987 — — ¹Geometric mean and coefficient of variation (%) wereadded to the summary statistics for AUCs and C_(max) only; << — >>: NotApplicable. N: Number of observations; SD: Standard Deviation; CV:Coefficient of variation; Min: Minimum; Max: Maximum. Treatment A:Baclofen tablets 20 mg. Treatment B: Baclofen granules 20 mg, withoutwater. Treatment C: Baclofen granules 20 mg, with water. Treatment D:Baclofen granules 20 mg, in soft food. Treatment E: Baclofen granules 20mg, with water, provided as 4 stick packs of 5 mg each.

Summary of Pharmacokinetic Parameters of Baclofen by Treatment-PerProtocol Population Treatment E Parameter Geo. Geo. (unit) N Mean Mean¹SD CV% CV%¹ AUC_(0-t) 28 2127.03 2090.93 419.84 19.74 18.63 (h*ng/mL)AUC_(0-∞) 28 2169.53 2134.91 416.63 19.20 18.00 (h*ng/mL) C_(max)(ng/mL) 28 322.12 318.39 48.32 15.00 15.97 t_(1/2) (h) 28 5.90 — 0.9516.18 — λ_(Z) (/h) 28 0.1206 — 0.0204 16.9493 — Parameter (unit) NMedian Min Max t_(max) (h) 28 1.489 0.736 2.998 — — ¹Geometric mean andcoefficient of variation (%) were added to the summary statistics forAUCs and C_(max) only; << — >>: Not Applicable. N: Number ofobservations; SD: Standard Deviation; CV: Coefficient of variation; Min:Minimum; Max: Maximum. Treatment A: Baclofen tablets 20 mg. Treatment B:Baclofen granules 20 mg, without water. Treatment C: Baclofen granules20 mg, with water. Treatment D: Baclofen granules 20 mg, in soft food.Treatment E: Baclofen granules 20 mg, with water, provided as 4 stickpacks of 5 mg each.

The following table summarizes parameters from Treatment Groups A-E forbaclofen.

Pharmacokinetic Parameters of Baclofen Subjects (No, (M/F) Type MeanParameters (+/−SD) Age: mean C_(max) T_(max)* AUC_(0-t) AUC_(0-∞)(Range) (ng/mL) (h) (h*ng/mL) (h*ng/mL) T_(1/2) (h) λ_(Z) (/h) 29(16M/13F) Treatment A Healthy 385.77 (+/− 0.995 (0.487, 2397.48 (+/−2454.57 (+/− 5.44 (+/− 0.1300 (+/− subjects 73.95) 2.990) 484.92)479.45) 0.80) 0.0190) 43.7 (20, 55) Treatment B 365.46 (+/− 1.487(0.737, 2396.45 (+/− 2443.30 (+/− 5.46 (+/− 0.1299 (+/− 67.79) 3.997)499.87) 488.86) 0.84) 0.0197) Treatment C 360.78 (+/− 1.486 (0.488,2362.06 (+/− 2407.31 (+/− 5.66 (+/− 0.1256 (+/− 72.40) 2.987) 425.92)417.25) 0.91) 0.0206) Treatment D 363.33 (+/− 1.488 (0.488, 2304.67 (+/−2345.11 (+/− 5.87 (+/− 0.1221 (+/− 59.94) 3.987) 446.28) 437.38) 1.10)0.0227) Treatment E 322.12 (+/− 1.489 (0.736, 2127.03 (+/− 2169.53 (+/−5.90 (+/− 0.1206 (+/− 48.32) 2.998) 419.84) 416.63) 0.95) 0.0204)*Median (Range: minimum and maximum values shown)

The PK values for the Treatment Groups A-E (M1 levels) are summarized inthe tables below.

Summary of Pharmacokinetic Parameters of Baclofen M1 by Treatment-PerProtocol Population Treatment A Treatment B Parameter Geo. Geo. Geo.Geo. (unit) N Mean Mean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t)29 780.27 730.41 269.84 34.58 40.03 29 775.94 738.46 241.19 31.08 33.54(h*ng/mL) AUC_(0-∞) 29 814.10 767.97 267.82 32.90 37.17 29 807.92 772.00242.13 29.97 31.98 (h*ng/mL) C_(max) (ng/mL) 29 56.76 54.92 14.30 25.1927.50 29 57.15 55.25 14.48 25.33 27.82 t_(1/2) (h) 29 8.18 — 1.79 21.89— 29 8.56 — 1.78 20.84 — λ_(Z) (/h) 29 0.0897 — 0.0242 26.9341 — 290.0849 — 0.0198 23.2954 — Parameter (unit) N Median Min Max N Median MinMax t_(max) (h) 29 5.988 3.986 5.998 — — 29 5.986 2.994 5.999 — —¹Geometric mean and coefficient of variation (%) were added to thesummary statistics for AUCs and C_(max) only; << — >>: Not Applicable.N: Number of observations; SD: Standard Deviation; CV: Coefficient ofvariation; Min: Minimum; Max: Maximum. Treatment A: Baclofen tablets 20mg. Treatment B: Baclofen granules 20 mg, without water. Treatment C:Baclofen granules 20 mg, with water. Treatment D: Baclofen granules 20mg, in soft food. Treatment E: Baclofen granules 20 mg, with water,provided as 4 stick packs of 5 mg each.

Summary of Pharmacokinetic Parameters of Baclofen M1 by Treatment-PerProtocol Population Treatment C Treatment D Parameter Geo. Geo. Geo.Geo. (unit) N Mean Mean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t)28 752.01 720.53 219.18 29.15 30.89 29 770.12 739.27 214.31 27.83 30.56(h*ng/mL) AUC_(0-∞) 28 793.87 764.56 216.78 27.31 28.94 29 814.39 784.38218.95 26.88 29.16 (h*ng/mL) C_(max) (ng/mL) 28 57.01 54.53 17.68 31.0231.42 29 55.87 54.23 13.00 23.27 26.53 t_(1/2) (h) 28 9.10 — 1.90 20.86— 29 9.37 — 2.78 30.68 — λ_(Z) (/h) 28 0.0800 — 0.0197 24.6353 — 290.0803 — 0.0228 28.3668 — Parameter (unit) N Median Min Max N Median MinMax t_(max) (h) 28 5.986 2.986 6.068 — — 29 4.005 2.988 6.153 — —¹Geometric mean and coefficient of variation (%) were added to thesummary statistics for AUCs and C_(max) only; << — >>: Not Applicable.N: Number of observations; SD: Standard Deviation; CV: Coefficient ofvariation; Min: Minimum; Max: Maximum. Treatment A: Baclofen tablets 20mg. Treatment B: Baclofen granules 20 mg, without water. Treatment C:Baclofen granules 20 mg, with water. Treatment D: Baclofen granules 20mg, in soft food. Treatment E: Baclofen granules 20 mg, with water,provided as 4 stick packs of 5 mg each.

Summary of Pharmacokinetic Parameters of Baclofen M1 by Treatment-PerProtocol Population Treatment E Parameter Geo. Geo. (unit) N Mean Mean¹SD CV% CV%¹ AUC_(0-t) 28 702.20 663.84 240.78 34.29 35.29 (h*ng/mL)AUC_(0-∞) 28 736.70 701.06 239.96 32.57 32.76 (h*ng/mL) C_(max) (ng/mL)28 49.05 47.50 11.89 24.23 27.46 t_(1/2) (h) 28 9.02 — 1.94 21.48 —λ_(Z) (/h) 28 0.0808 — 0.0196 24.2413 — Parameter (unit) N Median MinMax t_(max) (h) 28 4.990 2.987 6.001 — — ¹Geometric mean and coefficientof variation (%) were added to the summary statistics for AUCs andC_(max) only; << — >>: Not Applicable. N: Number of observations; SD:Standard Deviation; CV: Coefficient of variation; Min: Minimum; Max:Maximum. Treatment A: Baclofen tablets 20 mg. Treatment B: Baclofengranules 20 mg, without water. Treatment C: Baclofen granules 20 mg,with water. Treatment D: Baclofen granules 20 mg, in soft food.Treatment E: Baclofen granules 20 mg, with water, provided as 4 stickpacks of 5 mg each.

The following table summarizes parameters from Treatment Groups A-E forbaclofen metabolite M1.

Pharmacokinetic Parameters of M1 Subjects (No, (M/F) Type MeanParameters (+/−SD) Age: mean C_(max) T_(max)* AUC_(0-t) AUC_(0-∞)(Range) (ng/mL) (h) (h*ng/mL) (h*ng/mL) T_(1/2) (h) λ_(Z) (/h) 29(16M/13F) Treatment A Healthy 56.76 (+/− 5.988 (3.986, 780.27 (+/−814.10 (+/− 8.18 (+/− 0.0897 (+/− subjects 14.30) 5.998) 269.84) 267.82)1.79) 0.0242) 43.7 (20, 55) Treatment B 57.15 (+/− 5.986 (2.994, 775.94(+/− 807.92 (+/− 8.56 (+/− 0.0849 (+/− 14.48) 5.999) 241.19) 242.13)1.78) 0.0198) Treatment C 57.01 (+/− 5.986 (2.986, 752.01 (+/− 793.87(+/− 9.10 (+/− 0.0800 (+/− 17.68) 6.068) 219.18) 216.78) 1.90) 0.0197)Treatment D 55.87 (+/− 4.005 (2.988, 770.12 (+/− 814.39 (+/− 9.37 (+/−0.0803 (+/− 13.00) 6.153) 214.31) 218.95) 2.87) 0.0228) Treatment E49.05 (+/− 4.990 (2.987, 702.20 (+/− 736.70 (+/− 9.02 (+/− 0.0808 (+/−11.89) 6.001) 240.78) 239.96) 1.94) 0.0196) *Median (Range: minimum andmaximum values shown)

Ratios for the C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) can easily be calculated from theinformation in the tables above. For example, for Treatment Group B, theC_(max) value for baclofen (C_(max(baclofen))) is 365.46; the C_(max)value for M1 (C_(max(M1))) is 57.15; accordingly, 365.46/57.15 is 6.39,or 6.4 rounded up. Calculated ratios for other Treatment groups areshown in the table below.

Treatment C_(max(baclofen)):C_(max(M1)AUC_((0-t)(baclofen)):AUC_((0-t)(M1) B 6.4 3.1 C 6.3 3.1 D 6.5 3.0 E 6.63.0

Example 9 Food Effect on Pharmacokinetics

In order to evaluate whether administration with food affected PKparameters, the studies of Example 8 were generally repeated, but usingdifferent subjects and different treatments. The Treatment groups aresummarized in the table below.

Treatment Treatment Treatment Treatment A B C D Overall Number ofSubjects 29 26 27 27 29 Randomized Intent to Treat 29 (100) 26 (100) 27(100) 27 (100) 29 (100) population/Safety Population, N (%) Per Protocol28 (96.6) 26 (100) 27 (100) 27 (100) 28 (96.6) Population, N (%)Treatment A: Baclofen granules 20 mg, with water, fasted; Treatment B:Baclofen granules 20 mg, with water, fed; Treatment C: Baclofen granules5 mg, with water, fasted; Treatment D: Baclofen granules 10 mg, withwater, fasted. %: Number of subjects included compared to the number ofsubjects dosed.

For Treatment B, subjects were served a Food and Drug Administration(FDA) critical meal (high-fat, high-caloric breakfast) of between 800 to1000 calories (approximately 50% of total caloric content of the mealderived from fat). The breakfast was to consist of two eggs fried inbutter, two slices of toast with butter, two strips of bacon,approximately 120 g of hash brown potatoes, and 200 mL of whole milk.Subjects were served a controlled meal not less than 4.5 hours post-doseand at appropriate times thereafter. Subjects were served standardizedpost-dose meals similar in composition.

Treatments A, C, and D were generally treated as Treatment C asdescribed in Example 8 above. Treatments C and D were administered lowerdoses as noted in the table above.

The PK values obtained from these Treatment groups for baclofen areshown in the tables below.

Treatment A Treatment B Parameter Geo. Geo. Geo. Geo. (unit) N MeanMean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t) 28 2071.88 2056.13258.94 12.50 12.69 26 1860.01 1846.19 227.84 12.25 12.62 (h*ng/mL)AUC_(0-∞) 28 2137.24 2120.81 268.73 12.57 12.76 26 1912.74 1899.33228.40 11.94 12.23 (h*ng/mL) C_(max) (ng/mL) 28 342.12 339.53 41.3012.07 12.88 26 246.07 243.27 40.54 16.47 15.07 t_(1/2) (h) 28 5.37 —0.71 13.29 — 26 5.49 — 0.92 16.77 — λ_(Z) (/h) 28 0.1313 — 0.017012.9497 — 26 0.1295 — 0.0210 16.1995 — Parameter (unit) N Median Min MaxN Median Min Max t_(max) (h) 28 0.989 0.736 1.993 — — 26 2.986 0.7373.991 — — ¹Geometric mean and coefficient of variation (%) were added tothe summary statistics for AUCs and C_(max) only; << — >>: NotApplicable. N: Number of observations; SD: Standard Deviation; CV:Coefficient of variation; Min: Minimum; Max: Maximum. Treatment A:Baclofen granules 20 mg, with water, fasted. Treatment B: Baclofengranules 20 mg, with water, fed. Treatment C: Baclofen granules 5 mg,with water, fasted. Treatment D: Baclofen granules 10 mg, with water,fasted.

Treatment C Treatment D Parameter Geo. Geo. Geo. Geo. (unit) N MeanMean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t) 27 523.18 518.7567.06 12.82 13.61 27 1047.93 1040.54 128.22 12.24 12.13 (h*ng/mL)AUC_(0-∞) 27 542.58 537.98 69.40 12.79 13.63 27 1086.79 1079.00 133.4712.28 12.25 (h*ng/mL) C_(max) (ng/mL) 27 95.73 94.56 15.30 15.99 16.1427 191.26 188.54 32.83 17.17 17.48 t_(1/2) (h) 27 5.33 — 0.64 12.09 — 275.33 — 0.62 11.69 — λ_(Z) (/h) 27 0.1321 — 0.0167 12.6569 — 27 0.1318 —0.0163 12.3774 — Parameter (unit) N Median Min Max N Median Min Maxt_(max) (h) 27 0.987 0.486 1.987 — — 27 0.988 0.487 2.989 — — ¹Geometricmean and coefficient of variation (%) were added to the summarystatistics for AUCs and C_(max) only; << — >>: Not Applicable. N: Numberof observations; SD: Standard Deviation; CV: Coefficient of variation;Min: Minimum; Max: Maximum. Treatment A: Baclofen granules 20 mg, withwater, fasted. Treatment B: Baclofen granules 20 mg, with water, fed.Treatment C: Baclofen granules 5 mg, with water, fasted. Treatment D:Baclofen granules 10 mg, with water, fasted.

The PK values obtained from these Treatment groups for M1 are shown inthe tables below.

Treatment A Treatment B Parameter Geo. Geo. Geo. Geo. (unit) N MeanMean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t) 28 661.30 633.28191.70 28.99 31.54 26 578.06 559.31 151.54 26.21 26.73 (h*ng/mL)AUC_(0-∞) 28 730.40 703.96 194.64 26.65 29.06 26 651.82 632.24 172.8626.52 25.10 (h*ng/mL) C_(max) (ng/mL) 28 50.54 49.58 9.79 19.37 20.55 2637.13 36.28 8.94 24.08 21.24 t_(1/2) (h) 28 9.53 — 2.37 24.85 — 26 9.72— 2.12 21.84 — λ_(Z) (/h) 28 0.0760 — 0.0150 19.7111 — 26 0.0748 —0.0172 23.0202 — Parameter (unit) N Median Min Max N Median Min Maxt_(max) (h) 28 3.988 1.987 6.036 — — 26 5.988 3.987 7.959 — — ¹Geometricmean and coefficient of variation (%) were added to the summarystatistics for AUCs and C_(max) only; << — >>: Not Applicable. N: Numberof observations; SD: Standard Deviation; CV: Coefficient of variation;Min: Minimum; Max: Maximum. Treatment A: Baclofen granules 20 mg, withwater, fasted. Treatment B: Baclofen granules 20 mg, with water, fed.Treatment C: Baclofen granules 5 mg, with water, fasted. Treatment D:Baclofen granules 10 mg, with water, fasted.

Treatment C Treatment D Parameter Geo. Geo. Geo. Geo. (unit) N MeanMean¹ SD CV% CV%¹ N Mean Mean¹ SD CV% CV%¹ AUC_(0-t) 27 154.46 150.2937.34 24.17 24.13 27 322.27 312.78 80.67 25.03 25.35 (h*ng/mL) AUC_(0-∞)27 197.29 190.49 54.21 27.48 27.39 27 372.62 360.65 93.94 25.21 27.01(h*ng/mL) C_(max) (ng/mL) 27 13.47 13.08 3.46 25.69 24.81 27 25.46 25.015.03 19.76 19.15 t_(1/2) (h) 27 9.93 — 3.80 38.31 — 27 9.19 — 2.50 27.18— λ_(Z) (/h) 27 0.0773 — 0.0224 29.0166 — 27 0.0814 — 0.0235 28.8847 —Parameter (unit) N Median Min Max N Median Min Max t_(max) (h) 27 3.9872.987 6.015 — — 27 3.988 2.986 6.008 — — ¹Geometric mean and coefficientof variation (%) were added to the summary statistics for AUCs andC_(max) only; << — >>: Not Applicable. N: Number of observations; SD:Standard Deviation; CV: Coefficient of variation; Min: Minimum; Max:Maximum. Treatment A: Baclofen granules 20 mg, with water, fasted.Treatment B: Baclofen granules 20 mg, with water, fed. Treatment C:Baclofen granules 5 mg, with water, fasted. Treatment D: Baclofengranules 10 mg, with water, fasted.

Based on the results, dose proportionality of the PK was supportedacross the dose ranges of 5 mg, 10 mg, and 20 mg with water in a fastedstate.

Additionally, it can be concluded that food has a more pronounced effecton the rate (i.e., C_(max)) of absorption compared to the extent ofabsorption (AUCs) following administration of a single oral dose 20 mgdose of baclofen granules when administered with water (extent and rateof absorption decreased with food approximately 10% and 29%,respectively).

However, the ratios for the C_(max(baclofen)):C_(max(M1)) andAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) were apparently not significantlyaffected by administration with food. As shown in the table below, thefasted (Treatment A) versus fed (Treatment B) groups exhibited ratiosthat were generally consistent with Example 8 above.

Treatment C_(max(baclofen)):C_(max(M1)AUC_((0-t)(baclofen)):AUC_((0-t)(M1) A (20 mg Baclofen 6.8 3.1 granule,with water, fasted) B (20 mg Baclofen 6.6 3.2 granule, with water, fed

The present disclosure includes any combination of these variousfeatures or embodiments above and/or below as set forth in sentencesand/or paragraphs. Any combination of disclosed features herein isconsidered part of the present disclosure and no limitation is intendedwith respect to combinable features.

Applicant specifically incorporates the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the disclosure be limited to the specificvalues recited when defining a range.

Other embodiments of the present disclosure will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present disclosure disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the disclosure being indicated by thefollowing claims and equivalents thereof.

1. An oral granular pharmaceutical formulation comprising:4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or apharmaceutically acceptable salt thereof; wherein the formulation onadministration in human subjects under fasting conditions provides atime to maximum plasma concentration (Tmax) of about 1.5 hours or less.2. The formulation of claim 1, wherein the formulation on administrationin human subjects under fasting conditions provides an eliminationhalf-life (T½) of the baclofen or a pharmaceutically acceptable saltthereof of about 5.5 hours.
 3. The formulation of claim 1, wherein theformulation comprises a dose range of 5 mg, 10 mg, and 20 mg of baclofenor a pharmaceutically acceptable salt thereof.
 4. The formulation ofclaim 3, wherein the formulation on administration in healthy adultsubjects under fasting condition is dose proportional across the doserange.
 5. The formulation of claim 3, wherein the formulation comprises20 mg of baclofen or a pharmaceutically acceptable salt thereof.
 6. Theformulation of claim 5, wherein the formulation on administration inhuman subjects under fasting conditions provides a maximum plasmaconcentration (Geometric mean (% CV)) of the baclofen or apharmaceutically acceptable salt thereof of from about 318 (16%) toabout 379 (20%).
 7. The formulation of claim 6, wherein the formulationis administered 4 times a day to provide a total daily dose of 80 mg. 8.The formulation of claim 1, wherein the formulation comprises granulescomprising baclofen or a pharmaceutically acceptable salt thereof. 9.The formulation of claim 8, wherein the granules can be taken with orwithout water.
 10. The formulation of claim 8, wherein the granules areadministered via enteral feeding tube.
 11. The formulation of claim 8,wherein the granules are mixed with soft food for administration within2 hours.
 12. An oral granular pharmaceutical formulation comprising:4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or apharmaceutically acceptable salt thereof; wherein the formulation onadministration under high fat meal conditions to a human subject in needthereof results in a 10% decrease in AUC compared to administrationunder fasted conditions.
 13. An oral granular pharmaceutical formulationcomprising: 4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or apharmaceutically acceptable salt thereof; wherein the formulation onadministration under high fat meal conditions to a human subject in needthereof results in a 29% decrease in Cmax compared to administrationunder fasted conditions.
 14. A method of treating spasticity in a humansubject in need thereof comprising: administering to the subject an oralgranular pharmaceutical formulation comprising4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or apharmaceutically acceptable salt thereof; wherein the formulation onadministration to the subject provides an elimination half-life (T1/2)of the baclofen or a pharmaceutically acceptable salt thereof of about5.5 hours.
 15. The method of claim 14, wherein the spasticity resultsfrom multiple sclerosis.
 16. The method of claim 14, wherein thespasticity is associated with at least one of flexor spasms, pain,clonus, and muscular rigidity.
 17. The method of claim 14, wherein theeffective amount of baclofen is 20 mg.
 18. The method of claim 14,wherein the spasticity results from cerebral palsy, stroke, traumaticbrain injury, spinal cord injury, spinal cord disease, or combinationsthereof.
 19. A method of controlling exposure to baclofen metabolite3-(4-chlorophenyl) hydroxybutyric acid in a human subject comprising:administering to the subject an oral granular pharmaceutical formulationcomprising 4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or apharmaceutically acceptable salt thereof; wherein on administration tothe subject produces 3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as ametabolite in the patient; and wherein the formulation provides anAUC_((0-t)(baclofen)):AUC_((0-t)(M1)) ratio of about 3.1 and 3.2 underfasted and fed conditions respectively.
 20. The method of claim 19,wherein the AUC_((0-t)(baclofen)):AUC_((0-t)(M1)) ratios aresubstantially independent of presence or absence of food.